MOTS-C

Abstract

Prolonged exposure to high altitude (HA) results in a range of systemic changes, some of which, specifically for the heart, particularly cardiac changes, remain difficult to reverse after returning to low altitude. Cardiac de-acclimatization after HA exposure and its underlying mechanisms remain unclear. In this study, mice were subjected to a decompression chamber to simulate a 6000-m altitude exposure for 10 days, followed by the other 10-day de-acclimatization period at a lower altitude of 400 m. The cardiac dysfunction induced by HA exposure persisted throughout the de-acclimatization, accompanied with sustained mitochondrial dysfunction and the short peptide mitochondrial open reading frame of the 12S ribosomal RNA type-c (MOTS-c) deficiency. Exogenous supplementation of MOTS-c during de-acclimatization effectively alleviated the cardiac dysfunction post HA exposure. Mechanistically, MOTS-c activated the PTEN-induced putative kinase 1 (Pink1)/Parkin pathway, promoting mitophagy and improving mitochondrial quality. Silencing Pink1 abolished the protective effects of MOTS-c during de-acclimatization. Additionally, reduced circulating MOTS-c levels were observed in patients with high altitude heart disease and acute coronary syndrome. These results suggest that HA exposure leaves a memory of cardiac dysfunction upon return to lower altitude. This is attributed to a sustained deficiency in MOTS-c. MOTS-c maintains mitochondrial quality through promoting mitophagy, highlighting its therapeutic potential for treating HA-induced cardiac dysfunction during de-acclimatization.

Abstract

The mitochondrial-derived peptide MOTS-c regulates metabolic and cellular stress responses, but its dose-response profile and direct cardioprotective mechanisms in myocardial ischemia-reperfusion injury (MIRI) remain undefined. This proof-of-concept study aimed to identify the optimal cardioprotective dose of exogenous MOTS-c and delineate its multi-pathway mechanisms using an ex vivo rat heart IR model with in silico support. Isolated Langendorff-perfused rat hearts underwent 30-min global ischemia and 60-min reperfusion with or without MOTS-c (0.25-0.7 mg/kg) delivered via Krebs-Henseleit buffer during the first 10 min of reperfusion. Hemodynamics, infarct size (TTC), oxidative stress markers, inflammation, and apoptotic gene expression were quantified. Peptide-protein interactions with survival pathways were predicted computationally. MOTS-c at 0.5 mg per kg conferred maximal protection, producing a 73% reduction in infarct size compared with ischemia-reperfusion alone, improving heart rate, left ventricular developed pressure, and rate-pressure product, and lowering end-diastolic pressure. Lactate dehydrogenase release decreased by 65%. Antioxidant defenses improved with increased superoxide dismutase, catalase, and glutathione redox ratio, along with reduced lipid peroxidation. Myeloperoxidase activity normalized, pro-apoptotic genes including caspase 3, caspase 7, caspase 9, BAX, and PARP were downregulated, while cytoprotective genes including BCL2, GPX4, and FOXO were increased. Molecular docking demonstrated high-affinity interactions of MOTS-c with MAPK, mTOR, AMPK, NRF2, PI3K, and caspase 3. This ex vivo study identifies 0.5 mg/kg as the optimal dose within the tested range, producing coordinated anti-apoptotic, antioxidant, and anti-inflammatory effects. Although the isolated heart model isolates direct myocardial actions, the lack of systemic influences and limited dose range necessitate broader dosing and pharmacokinetic studies before translational application.

Abstract

Hepatocellular carcinoma (HCC), the most common primary liver cancer, is characterized by late diagnosis, limited treatment efficacy, and a highly immunosuppressive tumour microenvironment. Chronic liver injury, fibrosis, and inflammation are central to HCC pathogenesis, leading to genetic and epigenetic changes, particularly under oxidative stress from reactive oxygen species (ROS). Aberrant activation of pathways such as Wnt/β-catenin, contributes to uncontrolled proliferation, resistance to apoptosis, and metastasis. This review emphasizes how immunotherapy particularly immune checkpoint inhibitors and chimeric antigen receptor T (CAR-T) cell therapy, has reshaped HCC treatment approaches. Advances in CAR-T designs targeting antigens like GPC3, AFP, and PD-L1, have been engineered to address antigen heterogeneity, T-cell exhaustion, and poor tumour infiltration. Mutant p53 and PD-L1 in the tumour microenvironment pose challenges to therapy by suppressing T-cell activity. Furthermore, anticancer peptides (ACPs), such as Tv1, SHLP6, R-Tf-D-LP4, and MOTS-c, exhibit selective cytotoxicity, mitochondrial targeting, and disruption of tumour-promoting pathways. Nanotherapeutics like PIR NPs, ThermoDox, and liposomal drug formulations improve drug stability, delivery, and specificity, providing controlled release and reduced toxicity. The integration of CAR-T therapy with ACPs, nanomedicine, and dual-checkpoint blockade such as tremelimumab-durvalumab, and nivolumab-ipilimumab demonstrate improved tumour regression and survival outcomes. Combination strategies that modulate ROS levels, inhibit angiogenesis, and utilize peptide-drug conjugates show promise in preclinical and early clinical studies. This review highlights the therapeutic synergy of next-generation peptide, cellular, and nanoplatform-based therapies in enhancing outcomes for advanced HCC.

Abstract

MOTS-c (mitochondrial open reading frame of the 12S rRNA type-c) is a mitochondrial-derived peptide and regulator of metabolic homeostasis. Although its role in glucose and lipid metabolism is emerging, changes in circulating MOTS-c with obesity remain unclear. We hypothesized that circulating MOTS-c concentrations would be altered in obese vs. lean adults in associations with altered metabolic and inflammatory markers.

Abstract

Mitochondria-derived peptides (MDPs) are bioactive molecules encoded by small open reading frames within mitochondrial DNA (mtDNA). Humanin, the first MDP to be discovered, functions as a cytoprotective factor, protecting cells from stress-induced apoptosis. Subsequent discoveries expanded this family to include Mitochondrial Open-reading-frame of the Twelve S rRNA-c (MOTS-c), a key regulator of metabolic homeostasis and stress adaptation, and the Small Humanin-Like Peptides (SHLP1-6), which modulate mitochondrial bioenergetics and insulin sensitivity. MDPs play critical roles in liver homeostasis by maintaining mitochondrial function and metabolic balance. Intracellularly, they modulate mitochondrial activity, oxidative stress, and apoptosis, promoting hepatocyte survival. Extracellularly, they act in autocrine, paracrine, or endocrine manners, engaging receptors or signaling pathways to regulate nuclear gene expression and metabolic adaptation. Emerging evidence highlights their relevance in metabolic dysfunction-associated steatotic liver disease (MASLD). Humanin exerts hepatoprotective effects by inhibiting apoptosis and modulating lipid metabolism. MOTS-c activates AMPK, regulates nuclear gene expression, suppresses fibrotic and inflammatory signaling, and restores mitochondrial function in MASLD and fibrosis models. SHLPs, particularly SHLP2, enhance mitochondrial function and insulin sensitivity, supporting glucose homeostasis and mitigating oxidative stress. Collectively, MDPs establish a novel paradigm in mitochondrial signaling, extending mtDNA function beyond energy production. This review summarizes current insights into MDP biology and highlights its emerging therapeutic potential in chronic liver disease.

Abstract

Mitochondrial-derived peptides are a small class of regulatory peptides encoded by short open reading frames in mitochondrial DNA. One such peptide, mitochondrial open reading frame of the 12S rRNA-c (MOTS-c), has been shown to exert numerous beneficial effects on whole-cell and systemic metabolic parameters when administered exogenously. However, potential MOTS-c-mediated effects on mitochondrial bioenergetics have been largely overlooked. Therefore, the primary aim of the present study was to elucidate whether and, if so, how MOTS-c regulates skeletal muscle (SkM) mitochondrial function. We demonstrate, using two distinct transgenic mouse strains, that administration of MOTS-c augments muscle mitochondrial bioenergetic performance through reliance on both the transcriptional coactivator, Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), and cellular energy-sensing kinase, 5' adenosine monophosphate-activated protein kinase (AMPK). These effects seem to be exerted without apparent impact on mitochondrial respiratory protein content, alluding to intrinsic mitochondrial changes rather than changes in volume. Furthermore, MOTS-c treatment lowers mitochondrial reactive oxygen species (ROS) emission and ROS-related protein damage indicating substantial alleviation of cellular oxidative stress. RNA-sequence data reveal the effects of MOTS-c treatment to potentially be exerted subtly across a number of mitochondrial parameters such as redox handling, mitochondrial integrity and OXPHOS efficiency, jointly indicating a mechanistic basis for the observed functional improvements in mitochondrial bioenergetics. Despite increased interstitial MOTS-c levels no change was observed in the arterio-venous difference during one-legged knee extensor exercise in humans. This suggests that SkM may not be the source of circulating MOTS-c in response to exercise.

Abstract

This study evaluated whether serum levels of mitochondrial open reading frame of the 12S rRNA-c (MOTS-c) could provide prognostic insights in patients newly diagnosed with multiple myeloma (MM), particularly in relation to therapeutic responsiveness.

Abstract

Sarcopenia, a progressive skeletal muscle disorder marked by loss of mass and function, presents growing societal challenges due to limited therapeutic options. Here, we identify mitochondrial dysfunction and oxidative stress as central drivers of sarcopenia through integrated bioinformatics and clinical validation. To address this pathophysiology, we engineer a muscle-targeted nanocomposite (BP-PEG-MOTS-c, BM) combining mitochondrial-derived peptide MOTS-c with antioxidant black phosphorus nanosheets (BP). BM exhibits dual functionality: MOTS-c restores mitochondrial function, while BP synergistically amplifies ROS scavenging capacity. In cellular and murine models with age-related sarcopenia, BM treatment alleviates muscle dysfunction and muscle loss, concurrently normalizing mitochondrial function and reducing lipid peroxidation. Mechanistic profiling via RNA-seq reveals BM's activation of PI3K/AKT/Nrf2 and suppression of ROS/p38 MAPK signaling pathway, mediating antioxidant responses and maintenance of mitochondrial homeostasis. The nanocomposite demonstrats superior biocompatibility in toxicity assays, outperforming conventional delivery systems. Our findings establish that BM has been established as a promising mitochondrial redox modulator with translational potential for sarcopenia and related age-associated pathologies.

Abstract

Humanin (HN) and MOTS-c are mitochondrial-derived peptides (MDPs) known for their neuroprotective and metabolic functions. Their circulating and tissue levels decline with age and in neurodegenerative diseases such as Alzheimer's disease (AD). This study aimed to evaluate whether blood and plasma gene expression and plasma protein levels of HN and MOTS-c are associated with AD markers, their role in the conversion from mild cognitive impairment (MCI) to AD, and their overall association with the disease. A case-control study was conducted, including patients with AD and MCI, and individuals with subjective cognitive decline (SCD) as controls. Gene expression levels were quantified from total RNA isolated from blood and plasma, normalised to mitochondrial DNA copy number (mtDNA-CN). ELISA was used to measure plasma HN and MOTS-c protein concentrations. HN and MOTS-c transcript levels differed significantly among study groups, whereas plasma protein concentrations did not discriminate between AD and MCI. In silico and RNA decay assays revealed faster degradation of HN mRNA and delayed but stable recovery of MOTS-c mRNA. Overall, blood and plasma transcript levels-but not circulating protein levels-of these MDPs were significantly reduced in AD compared to SCD, suggesting their potential as early biomarkers of Alzheimer's disease.

Abstract

Intrauterine growth restriction (IUGR) is a leading cause of perinatal morbidity and mortality. Oxidative stress is a key factor in the pathogenesis of IUGR. The transcription factor nuclear factor erythroid 2‑related factor 2 (Nrf2) is a key regulator of the cellular antioxidant response. MOTS‑c, a 16‑amino acid peptide derived from the mitochondria, regulates oxidative stress related pathways. However, the effects of MOTS‑c on IUGR remain unclear. The present study aimed to investigate the role of MOTS‑c in hypoxia‑induced placental restriction and IUGR and its underlying mechanisms. Wild‑type and Nrf2 knockout (KO) maternal mice were exposed to hypoxia from gestational days 11 to 17.5 to establish the IUGR model. Human umbilical vein endothelial cells (HUVECs) were used for in vitro assays. Maternal serum and placenta MOTS‑c concentration were measured using an enzyme‑linked immunosorbent assay. Hematoxylin and eosin staining, reverse transcription‑quantitative PCR, western blotting, immunohistochemistry and immunofluorescence techniques were employed to evaluate the effects of MOTS‑c treatment on IUGR. It was found that reduced placental content of MOTS‑c was positively correlated with low fetal weight in mice with hypoxia‑induced IUGR. The administration of MOTS‑c (5 mg/kg) significantly attenuated hypoxia‑induced IUGR by promoting placental angiogenesis and inhibiting oxidative stress‑mediated placental dysfunction. Furthermore, these protective effects exerted by MOTS‑c were dependent on Nrf2 activation, as administration of MOTS‑c had no protective role in Nrf2 KO mice or HUVECs pre‑treated with ML385, a Nrf2 inhibitor. Taken together, the present study demonstrated that MOTS‑c mitigated placental injury in hypoxia‑induced IUGR by activation of the Nrf2 signaling pathway, thus potentially identifying a novel therapeutic strategy for hypoxia‑induced IUGR.

Abstract

Diabetes mellitus is a major global health issue with complex aetiology and a higher risk of consequent health complications. Advances in research and knowledge prompt new therapies to focus beyond glycemic control to include organ-protective therapies better optimise treatment outcomes. MOTS-c, a recently discovered mitochondria-derived peptide, plays a key role in regulating metabolic homeostasis and stress response. Emerging evidence suggests that insufficient MOTS-c production from dysfunctional mitochondria contributes to the pathological development of diabetes and its complications through its regulatory effects on cellular retrograde signalling. This review systematically classifies and analyses the various associations of MOTS-c with T2DM risk factors and summarises the relevant changes in a novel tabular format. In addition, the key role of MOTS-c in the major diabetes-related complications is specifically explored, with a special focus on its protective and therapeutic potential in diabetic cardiomyopathy. Beyond summarising its multifaceted roles, this review also uniquely compiles and discusses the distinct exogenous MOTS-c therapeutic approaches, including varying doses and dosing schedules, applied in preclinical metabolic disease studies, thereby providing valuable insights into future translational research.

Abstract

Osteoarthritis, a common chronic degenerative disease in the field of orthopedics, is caused by the interaction of mechanical stress, traumatic inflammation, and metabolic imbalance, and this interaction progresses over time. MOTS-c, a mitochondria-derived peptide, exerts pivotal roles in regulating metabolism, anti-inflammation, and antioxidant stress responses. However, current research on the role of MOTS-c in osteoarthritis remains scarce, and its specific mechanism of action remains unclear. Therefore, this study aims to further explore the molecular mechanisms by which MOTS-c regulates osteoarthritis. Exogenous supplementation of MOTS-c improves mitochondrial dysfunction, inhibits the activation of inflammatory bodies and rescues chondrocyte pyroptosis, thereby regulating the metabolic balance of extracellular matrix (ECM). Mechanistically, MOTS-c plays a key role in LPS-induced oxidative stress and chondrocyte pyroptosis through the Nrf2/TXNIP/NLRP3 axis. Our research demonstrates that MOTS-c can not only effectively inhibit the expression of inflammatory factors but also promote the expression of major components of the extracellular matrix (ECM) and suppress the production of matrix metalloproteinases. We validated the in vivo efficacy of MOTS-c by establishing a murine osteoarthritis model. Analysis of imaging and histopathological results revealed that MOTS-c can effectively delay the degeneration of articular cartilage and ameliorate the progression of osteoarthritis. Collectively, our findings uncover the intrinsic regulatory mechanism of MOTS-c in chondrocytes and its potential value in the treatment of osteoarthritis.

Abstract

To investigate the Mitochondrial Open Reading Frame of the 12S rRNA type-c (MOTS-c) peptide levels in individuals with obesity compared to those with a normal body mass index and to examine the association of MOTS-c levels with markers of insulin resistance, endothelial function, and inflammation.

Abstract

Regular physical activity induces a dynamic crosstalk between skeletal muscle and adipose tissue, modulating the key molecular pathways that underlie metabolic flexibility, mitochondrial function, and inflammation. This review highlights the role of myokines and adipokines-particularly IL-6, irisin, leptin, and adiponectin-in orchestrating muscle-adipose tissue communication during exercise. Exercise stimulates AMPK, PGC-1α, and SIRT1 signaling, promoting mitochondrial biogenesis, fatty acid oxidation, and autophagy, while also regulating muscle hypertrophy through the PI3K/Akt/mTOR and Wnt/β-catenin pathways. Simultaneously, adipose-derived factors like leptin and adiponectin modulate skeletal muscle metabolism via JAK/STAT3 and AdipoR1-mediated AMPK activation. Additionally, emerging exercise mimetics such as the mitochondrial-derived peptide MOTS-c and myostatin inhibitors are highlighted for their roles in increasing muscle mass, the browning of white adipose tissue, and improving systemic metabolic function. The review also addresses the role of anti-inflammatory compounds, including omega-3 polyunsaturated fatty acids and low-dose aspirin, in mitigating NF-κB and IL-6 signaling to protect mitochondrial health. The resulting metabolic flexibility, defined as the ability to efficiently switch between lipid and glucose oxidation, is enhanced through repeated exercise, counteracting age- and disease-related mitochondrial and functional decline. Together, these adaptations demonstrate the importance of inter-tissue signaling in maintaining energy homeostasis and preventing sarcopenia, obesity, and insulin resistance. Finally, here we propose a stratified treatment algorithm based on common age-related comorbidities, offering a framework for precision-based interventions that may offer a promising strategy to preserve metabolic plasticity and delay the age-associated decline in cardiometabolic health.

Abstract

Mitochondria are crucial for cell survival and function, partly through peptides encoded by the mitochondrial genome. Although mitochondrial dysfunction is a hallmark of age-related diseases and senescence, the role of mitochondrial-genome-encoded peptides in pancreatic β-cell senescence during type 1 and type 2 diabetes pathogenesis is largely unexplored. Here we show that MOTS-c levels decrease with aging and senescence in pancreatic islet cells. Treating aged C57BL/6 mouse pancreatic islets with MOTS-c reduced pancreatic islet senescence by modulating nuclear gene expression and metabolites involved in β-cell senescence. MOTS-c treatment improved pancreatic islet senescence and glucose intolerance in S961-treated C57BL/6 and in nonobese diabetic mice. In humans, circulating MOTS-c levels are lower in type 2 diabetes patients compared with healthy controls. Our findings suggest that mitochondrial-encoded MOTS-c regulate pancreatic islet cell senescence and that MOTS-c could act as a senotherapeutic agent to prevent pancreatic islet cell senescence and diabetes progression.

Abstract

Acute coronary syndrome (ACS) is a coronary emergency that arises from myocardial ischemia and thrombosis and can be triggered by the rupture of a subcutaneous unstable plaque within the coronary artery or coronary artery erosion. The current study aimed to calculate the predictive value of serum angiopoietin 2 (Ang-2) and cystatin C (Cys-C) levels in the early diagnosis of ACS. We retrospectively analyzed data from 180 patients diagnosed with ACS at our hospital between January 2023 and June 2024, with 120 healthy volunteers serving as the control group during the same period. Clinical baseline and pathological data were recorded for all participants, and serum levels of Ang-2 and Cys-C were determined using an enzyme-linked immunosorbent assay kit. The correlation between serum Ang-2, Cys-C levels, and Gensini scores in patients with ACS was analyzed using Spearman or Pearson correlation coefficients, respectively. Independent risk factors for ACS were analyzed using multivariate logistic regression. A receiver operating characteristic curve was used to analyze the predictive value of serum Ang-2, Cys-C, or Ang-2 combined with Cys-C for the early diagnosis of ACS. Serum Ang-2 and Cys-C levels in patients with ACS were significantly higher than those in the normal group. Serum Ang-2 and Cys-C levels significantly and positively correlated with Gensini scores in patients with ACS. Logistic multivariate regression analysis revealed that total cholesterol, triglycerides, low-density lipoprotein cholesterol, Ang-2, and Cys-C were independent risk factors for ACS. The area under the curve of serum Ang-2 combined with Cys-C was 0.897 (sensitivity, 77.22%; specificity, 87.50%) in patients with ACS, and its diagnostic efficacy was higher than that of Ang-2 or Cys-C alone. Serum Ang-2 and Cys-C are highly expressed in patients with ACS, and serum Ang-2 combined with Cys-C has a high predictive value for the early diagnosis of ACS.

Abstract

MOTS-c is a mitochondrial peptide that plays a crucial role in regulating energy metabolism, gene expression, and immune processes. However, current research primarily focuses on mammals like humans and mice, with no reports on avian MOTS-c. This study aimed to identify and characterize MOTS-c coding sequences across major poultry species through bioinformatics analysis and experimental validation. The alignment results showed high sequence similarity in the MOTS-c coding regions between avian and mammalian species. However, a single nucleotide deletion was identified in avian sequences at the position corresponding to the fourth amino acid residue of mammalian homologs, resulting in divergent downstream amino acid sequences. Despite this deletion, several residues were conserved across species. Phylogenetic analysis of mRNA sequences grouped pigeons with mammals, while protein sequence analysis revealed that poultry and mammals form separate branches, highlighting the divergence between avian and mammalian MOTS-c sequences. Tissue expression profiling demonstrated widespread distribution of chicken MOTS-c across multiple tissues, with the highest expression levels in the heart. Fasting significantly reduced heart MOTS-c expression, suggesting potential metabolic regulatory functions. Functional analysis of MOTS-c in primary hepatocytes revealed significant enrichment of the ribosome, oxidative phosphorylation, and key signaling pathways (PI3K-AKT and JAK-STAT) following 24 hours of treatment. Western blot validation confirmed MOTS-c-mediated activation of the AKT signaling pathway. This study represents the first comprehensive characterization of avian MOTS-c, providing critical insights into its evolutionary conservation and its potential functional roles in gene expression and cellular metabolism. Our findings establish a foundation for further investigation into the functions of mitochondrial-encoded peptides in avian species.

Abstract

This study aimed to evaluate the diagnostic significance of circulating mitochondrial-derived peptides, Humanin and MOTS-c, the long non-coding RNA GAS5, and exosomal microRNAs miR-21 and miR-103 in stratifying prostate diseases, including benign prostatic hyperplasia (BPH), precancerous lesions (PL), and prostate cancer (PCa). These biomarkers were selected based on their established roles in cellular stress responses, apoptosis regulation, inflammation, and tumor progression. A cohort of 375 male patients suspected of prostate cancer were enrolled. Plasma and exosomal levels of Humanin, MOTS-c, GAS5, miR-21, and miR-103 were measured. Diagnostic performance was assessed using receiver operating characteristic (ROC) curve analysis, principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), and decision tree models. Results showed significant downregulation of Humanin and GAS5 in both PL and PCa compared to BPH, supporting their role in early disease transition. Exosomal miR-21 and miR-103 were significantly upregulated in PCa, with miR-21 exhibiting outstanding discriminative power between BPH and PL (AUC = 1.000) and between PL and PCa (AUC = 0.9932). MOTS-c, a mitochondrial-derived peptide, displayed elevated levels in PL compared to BPH, suggesting its involvement in early malignant transformation. A plasma-only diagnostic model combining Humanin, GAS5, and MOTS-c reached 95% cross-validated classification accuracy across clinical groups. Combination of circulating Humanin, MOTS-c, GAS5, and exosomal miRNAs provides a promising non-invasive biomarker panel for risk stratification in prostate diseases. This integrated molecular approach may enhance diagnostic precision and guide personalized clinical decision-making in prostate cancer management.

Abstract

Sepsis-associated encephalopathy (SAE) is a serious complication of sepsis, increasing short-term and long-term mortality. It involves neuroinflammation, neuronal damage, and blood-brain barrier (BBB) disruption. MOTS-c, a mitochondrion-derived peptide, exerts neuroprotective effects by modulating inflammatory responses and cellular functions. This study explored the protective effects of MOTS-c against brain injury in mice with LPS-induced sepsis.

Abstract

Mitochondrial-derived peptides (MDPs), including humanin, MOTS-c, and small humanin-like peptides (SHLPs), have emerged as promising therapeutic candidates for neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). This review systematically evaluates current literature retrieved from databases including PubMed, Scopus, and Web of Science using keywords such as "mitochondrial-derived peptides," "neurodegeneration," "humanin," "MOTS-c," and "SHLPs." Studies were included based on their relevance to mitochondrial function, oxidative stress, neuroprotection, and anti-inflammatory mechanisms in AD, PD, and HD models. Despite growing interest, current research remains limited in understanding the precise molecular pathways. Our review highlights their role in mitigating disease-specific pathologies such as Amyloid-beta (Aβ) toxicity in AD, dopaminergic neuron loss in PD, and mutant huntingtin aggregation in HD while also emphasizing their potential to attenuate oxidative stress and neuroinflammation. By identifying critical knowledge gaps, particularly in the areas of molecular mechanisms of MDPs in neuroprotection, targeted delivery, and clinical translation, this review provides a comprehensive framework to guide future investigations.

Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disorder and mainly occurs in people above the age of 60 years. It is defined by the progressive degeneration of dopaminergic neurons of the substantia nigra pars compacta, which results in the classic motor symptoms. Though aggregation of alpha-synuclein and Lewy body formation are still the core of the disease pathogenesis, PD pathogenesis is complex with mitochondrial dysfunction, oxidative stress, neuroinflammation, impaired autophagy, and endoplasmic reticulum (ER)-Golgi stress. Of these, mitochondrial dysfunction has been the focus of special interest because of its key function in energy metabolism and generation of reactive oxygen species (ROS), which can hasten the neuronal damage. Over the past few years, mitochondrial-derived peptides (MDPs), also k/a mitochondrial microproteins such as Humanin, Small Humanin-Like Peptides (SHLPs), and Mitochondrial Open Reading Frame of the 12S rRNA type-c (MOTS-c) have been identified as new hope for modulating cellular stress responses. Their therapeutic opportunities to impact major pathogenic processes in PD, including inflammation, oxidative stress, and metabolic dysfunction, make them new targets for disease-modifying therapies. With the escalating load of PD and the limitation of existing symptomatic therapies, novel molecular targets need to be explored urgently. Research into the mechanisms involving MDPs in PD not only enhances the insight into disease mechanisms but could potentially lead the way toward next-generation therapies. This article is intended to thoroughly review the role of MDPs in PD pathogenesis and highlight their importance as novel therapeutic agents. With the growing burden of PD and the absence of disease-modifying therapies, exploring novel mitochondrial signaling pathways offers an urgently needed therapeutic direction.

Abstract

Heat stress, like exercise, can elicit beneficial mitochondrial adaptations and attenuate disuse muscle atrophy. The beneficial effects of heat therapy may in part be related to mitokines as they are released by the cells in response to perceived mitochondrial stress. This study thus investigated the effect of repeated heat exposures on mitokine response in the context of immobilization-induced muscle atrophy.

Abstract

Type 2 diabetes (T2D) is a global epidemic, and heart failure is the primary cause of premature death among T2D patients. Mitochondrial dysfunction has been linked to decreased contractile performance in diabetic heart, partly due to a disturbance in the mitochondrial capacity to supply adequate metabolic energy to contractile proteins. MOTS-c, a newly discovered mitochondrial-derived peptide, has shown promise as a therapeutic for restoring energy homeostasis and muscle function in metabolic diseases. However, whether MOTS-c therapy improves T2D heart function by increasing mitochondrial bioenergetic function remains unknown.

Abstract

The aim of the study was to investigate the effect of MOTS-c on the key functional alterations in the rat soleus muscle during 7-day unloading - the transformation of slow fibers into fast ones, atrophy and increased fatigue. We daily intraperitoneally injected male Wistar rats with a short mitochondrial peptide MOTS-c during 7-day unloading of their hind limbs. After the end of the experiment, we conducted an ex vivo fatigue test of soleus muscle and showed that the MOTS-c administration prevents increased fatigue during 7-day hind limb unloading. Also, using immunohistochemical analysis, we showed that MOTS-c prevents the transformation of slow fibers into fast ones, mitigates the slow muscle atrophy fibers (but not fast ones) of the soleus muscle. In the group receiving MOTS-c, the decrease in Akt and GSK3β phosphorylation was prevented, and the 18 S and 28 S rRNA levels were at the control level. The ubiquitin ligases MuRF and Atrogin-1 mRNA were also reduced compared to the hindlimb unloading group with placebo. In addition, MOTS-c prevented a decrease in the expression of a few mitochondrial biogenesis parameters and the level of ACC phosphorylation (AMPK target). Thus, the MOTS-C injections during hind limb unloading lead to the normalization of several protein synthesis and degradation processes and support the expression of genes that ensure muscle resistance to fatigue.

Abstract

Vascular aging profoundly affects the onset of cardiovascular diseases in the elderly, mostly as a result of mitochondrial dysfunction. This review examines the protective roles of mitochondrial-derived peptides such as humanin, MOTS-c, and small humanin-like peptides in mitigating vascular aging. These peptides, encoded by mitochondrial DNA, are crucial for regulating apoptosis, inflammation, and oxidative stress, which have a major role in vascular health. MDPs have significant prospects as therapeutic and biomarker possibilities for the early diagnosis and intervention of vascular aging. MDPs influence the functions of endothelial and vascular smooth muscle cells by modulating critical signaling pathways, including AMPK, mTOR, and sirtuins. These pathways are essential for facilitating cellular metabolism, enhancing stress resilience, and prolonging longevity. Moreover, MDPs are essential in mitochondrial bioenergetics and dynamics, vital for mitigating endothelial dysfunction and enhancing vascular resilience. Furthermore, MDPs contribute to immunological modulation and the regulation of inflammatory responses, underscoring their potential therapeutic applications in the treatment of age-related vascular disorders. This review analyzes the various functions of MDPs in vascular health and their therapeutic importance, advocating for more studies to optimize their clinical benefits. By understanding the comprehensive roles and mechanisms of these multifunctional peptides, we can better appreciate their capacity to prevent and treat vascular aging and associated cardiovascular disorders. Future research should aim to further elucidate their therapeutic effects and optimize their clinical applications.

Abstract

Recent research has identified the mitochondrial open reading frame of the 12S rRNA-c (MOTS-c) as a crucial mitochondrial peptide that significantly influences metabolic regulation, mimics the effects of exercise, and mitigates oxidative stress. This study aims to investigate the relationship between serum MOTS-c levels and obstructive sleep apnea (OSA) to enhance our understanding of the disease's pathophysiology. By elucidating this relationship, we hope to uncover new insights into the mechanisms underlying OSA and its associated metabolic complications. Seventy-seven participants were enrolled in this study, including 53 patients with OSA and 24 controls. We measured serum MOTS-c levels and collected participants' demographic characteristics, polysomnography (PSG) data, complete blood count (CBC) data, and sleep-related questionnaires. The study included 77 participants, consisting of 8 patients with mild OSA, 16 with moderate OSA, 29 with severe OSA, and 24 controls. The cohort comprised 26 women and 51 men. Analysis revealed that serum MOTS-c levels were significantly correlated with BMI, AHI (Apnea-Hypopnea Index), and ODI (Oxygen Desaturation Index), independent of age. Additionally, the severity of OSA was inversely related to serum MOTS-c levels, with lower levels observed in patients with more severe OSA. Variations in serum MOTS-c levels were also noted across different BMI classifications. Analysis of covariance (ANCOVA), with BMI as a covariate, demonstrated that the severity of OSA was an independent factor influencing serum MOTS-c levels. Serum MOTS-c levels correlate with both severity of OSA and BMI classification, suggesting that MOTS-c may have significant therapeutic potential for treating OSA.

Abstract

Intervertebral disc degeneration (IDD) is characterized by oxidative-stress driven progressive apoptosis and senescence of nucleus pulposus mesenchymal stem cells (NP-MSCs). MOTS-c, a 16-amino acid peptide encoded by the mitochondrial 12S rRNA open reading frame, has emerged as a key regulator of cellular metabolism, oxidative stress, and senescence. This study investigated the therapeutic potential of MOTS-c in countering tert-butyl hydroperoxide (TBHP)-induced oxidative damage in NP-MSCs, and we developed a novel biomaterial strategy for IDD treatment.Key findings include.

Abstract

MOTS-c is a promising regulator of metabolism and energy homeostasis. While its effects have been studied in cell lines, our team aimed to investigate its influence on more complex structures-specifically, isolated pancreatic islets. We used two animal models: the rat, which is commonly studied, and the pig, which shares greater physiological similarities with humans. This study assessed the expression and secretion of insulin and glucagon, the expression of their receptors, cell viability, and cell death following MOTS-c treatment of the islets. Additionally, we examined how MOTS-c secretion is affected by different incubation media, such as the presence of free fatty acids, pancreatic hormones, and different glucose concentrations. The results indicate that MOTS-c impacts pancreatic islet physiology by, for example, reducing insulin and glucagon secretion and enhancing cell viability. Notably, the effects differed between the two species, which may be attributed to anatomical differences in their pancreatic islets or structural variations in rat and pig MOTS-c. These facts may lead to the conclusion that if MOTS-c may be helpful in human medicine, the pig model should be considered another valuable choice.

Abstract

Liver fibrosis is a common complication of T2DM(Type 2 diabetes mellitus). Appropriate intervention (exercise or drugs) in the early stage of liver fibrosis can slow down or even reverse liver fibrosis. MOTS-c (Mitochondrial open reading frame of the 12 S r RNA type-c ) has been described as an exercise-mimicking substance, and its effects are similar to those achieved by aerobic exercise; however, the exact mechanism remains to be elucidated. In this study, liver function was impaired in a T2DM rat model, leading to the aggravation of liver fibrosis. T2DM rats with liver fibrosis were subjected to MOTS-c, aerobic exercise therapy, or their combination. HE staining, Masson's trichrome staining and immunohistochemistry were used for histopathological examination. Transcriptome sequencing, q-PCR and WB were used to detect the expression of Keap1 (Kelch-like ECH-associated protein 1), Nrf2 (Nuclear factor erythroid 2-related factor 2 ), Smad2/3/4 and other genes. MOTS-c and aerobic exercise therapy improved T2DM-induced liver fibrosis. Additionally, cells were transfected with MOTS-c overexpression or interference plasmids or MOTS-c was added to the culture medium. MOTS-c overexpression or MOTS-c addition to the culture medium inhibited ROS levels, increased the mRNA and protein expression of Keap1-Nrf2 pathway genes and decreased the expression of TGF-β1(Transforming growth factor-beta1)/Smad pathway genes. Our findings demonstrate that MOTS-c modulates the progression of T2DM complicated by liver fibrosis through a Keap1-Nrf2-Smad2/3 signaling pathway-dependent mechanism.