MOTS-C

1. Introduction

The biological understanding of the mitochondrion has undergone a seismic shift in the last decade, transitioning from a reductionist view of the organelle as merely a cellular power plant to a sophisticated, integrated signaling hub governing organismal homeostasis. For nearly half a century, the dogma persisted that the human mitochondrial genome (mtDNA)—a circular, double-stranded DNA molecule of approximately 16.6 kilobases—functioned solely to encode thirteen distinct protein subunits essential for the electron transport chain (ETC) and oxidative phosphorylation (OXPHOS), alongside the necessary transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs) for their intra-mitochondrial translation.1 Regions outside these known coding sequences were largely dismissed as non-coding or vestigial remnants of the organelle’s alpha-proteobacterial endosymbiotic origin.1

This paradigm was irrevocably altered by the discovery of Mitochondrial-Derived Peptides (MDPs), a class of bioactive peptides encoded by short open reading frames (sORFs) within the mitochondrial genome. The identification of Humanin in 2001 provided the first evidence of this hidden coding capacity, but it was the isolation and characterization of the Mitochondrial Open Reading Frame of the 12S rRNA-c (MOTS-c) in 2015 that fundamentally expanded the frontiers of metabolic physiology.2 Unlike structural proteins restricted to the mitochondrial matrix, MOTS-c acts as a “mitokine”—a soluble, hormone-like signaling factor that translocates to the nucleus and circulates systemically to orchestrate broad metabolic adaptations.4

This report presents an exhaustive, expert-level analysis of MOTS-c, synthesizing data from molecular biochemistry, preclinical mammalian models, and emerging human clinical trials. It explores the peptide’s potential as a therapeutic agent for metabolic syndrome, sarcopenia, and age-related decline, while critically evaluating the safety profile and the nascent body of anecdotal evidence surrounding its off-label use in humans.

2. Genomic Architecture and Biosynthesis

2.1 The “Ghost” in the Genome

MOTS-c is a 16-amino acid peptide (Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg) encoded by a sORF within the 12S rRNA gene (MT-RNR1) of the mitochondrial genome.3 The existence of this peptide challenges the canonical rules of genetics in two distinct ways. First, the 12S rRNA gene was historically considered non-coding RNA, serving only structural and catalytic roles in the mitochondrial ribosome. The discovery that this sequence also harbors genetic information for a translatable peptide implies a dual-functionality—acting as both RNA machinery and messenger RNA (mRNA)—a phenomenon rarely observed in eukaryotic biology.1

Second, the translation of MOTS-c appears to occur in the cytosol, not within the mitochondria. Standard mitochondrial translation utilizes a distinct genetic code (e.g., UGA codes for Tryptophan rather than a stop codon). However, the MOTS-c sequence obeys the standard nuclear genetic code.2 This necessitates the export of the MOTS-c transcript from the mitochondrial matrix into the cytoplasm, a complex translocation event that remains only partially understood but underscores the intense integration between mitochondrial and nuclear compartments.6

2.2 Evolutionary Conservation and Structure

The MOTS-c sequence, particularly the N-terminal hydrophobic core, is highly conserved across 14 mammalian species, suggesting a potent evolutionary pressure to maintain its physiological function.7 The peptide sequence (MRWQEMGYIFYPRKLR) forms an amphipathic helix, a structural motif common among bioactive peptides that interact with membranes or receptors. Its molecular weight is approximately 2174.7 Daltons.8 The hydrophobic residues (specifically 8-YIFY-11) are critical not only for its stability but also for its ability to traverse cellular compartments, including its retrograde translocation into the nucleus.9

3. Molecular Pharmacodynamics and Signaling Pathways

The physiological potency of MOTS-c stems from its ability to hijack and modulate ancient metabolic pathways. It functions as a mimetic of metabolic stress, triggering “mitohormesis”—a biological response where low levels of mitochondrial stress elicit protective, adaptive systemic effects.

3.1 The Folate-AICAR-AMPK Axis

The primary and most distinct mechanism of action for MOTS-c is its interference with the folate cycle, which serves as the biochemical trigger for its metabolic effects.

3.1.1 Inhibition of the Folate Cycle

Upon entering the cytoplasm, MOTS-c inhibits the folate cycle at the level of 5-methyltetrahydrofolate (5-methyl-THF). The folate cycle is inextricably linked to de novo purine biosynthesis, which provides the nucleotides (adenine and guanine) necessary for DNA and RNA synthesis.1 By restricting this cycle, MOTS-c creates a bottleneck in purine synthesis.11

3.1.2 Accumulation of AICAR

The blockade of purine biosynthesis leads to the intracellular accumulation of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an intermediate metabolite.12 Under normal conditions, AICAR is rapidly converted to FAICAR and subsequently to inosine monophosphate (IMP). However, in the presence of MOTS-c, AICAR levels rise significantly. AICAR is a structural analog of adenosine monophosphate (AMP).13

3.1.3 Activation of AMPK

The accumulated AICAR acts as a potent agonist of AMP-activated protein kinase (AMPK), the cell’s master metabolic sensor. AMPK is a heterotrimeric complex that monitors the cellular AMP:ATP ratio. When AICAR binds to the gamma-subunit of AMPK, it induces a conformational change that promotes the phosphorylation of Threonine-172 on the alpha-subunit by upstream kinases (such as LKB1). This activation occurs even in the absence of actual energy depletion, effectively “tricking” the cell into a state of perceived metabolic stress.12

Once activated, AMPK initiates a cascade of phosphorylation events:

Inhibition of Anabolism: It phosphorylates and inhibits Acetyl-CoA Carboxylase (ACC), the rate-limiting enzyme in fatty acid synthesis (lipogenesis).12
Stimulation of Catabolism: It promotes fatty acid oxidation (beta-oxidation) and glucose uptake.
Mitochondrial Biogenesis: It activates PGC-1α (Peroxisome proliferator-activated receptor-gamma coactivator 1-alpha), driving the production of new mitochondria.12

This Folate-AICAR-AMPK mechanism distinguishes MOTS-c from other metabolic agents. While metformin also activates AMPK, it does so primarily by inhibiting Complex I of the ETC; MOTS-c achieves this via direct metabolic modulation of the folate pool.6

3.2 Nuclear Translocation and Transcriptional Control

In response to systemic metabolic stress (e.g., glucose restriction, oxidative stress, or intense exercise), MOTS-c translocates from the cytoplasm into the nucleus. This translocation is dependent on the hydrophobic motif (YIFY) within the peptide.9

Inside the nucleus, MOTS-c does not merely act as a cofactor but binds directly to chromatin. It targets Antioxidant Response Elements (ARE) in the promoter regions of genes regulated by the NRF2 (Nuclear Factor Erythroid 2-Related Factor 2) pathway.1 NRF2 is the primary regulator of cellular resistance to oxidants. By enhancing ARE binding, MOTS-c upregulates the expression of cytoprotective enzymes (e.g., Heme Oxygenase-1, Superoxide Dismutase), thereby conferring resistance to oxidative stress.14 This nuclear role classifies MOTS-c as a retrograde signaling molecule, facilitating communication from the mitochondria (the site of stress sensing) to the nucleus (the site of adaptive gene expression).4

3.3 The Myostatin Inhibition Pathway (CK2-PTEN-AKT-FOXO1)

A critical discovery regarding MOTS-c’s effect on skeletal muscle involves its interaction with the myostatin signaling network. Myostatin (GDF-8) is a TGF-beta superfamily member that acts as a negative regulator of muscle mass; its inhibition leads to muscle hypertrophy. MOTS-c suppresses myostatin via a specific kinase cascade:

CK2 Activation: MOTS-c enhances the activity of Casein Kinase 2 (CK2).15
PTEN Inhibition: CK2 phosphorylates Phosphatase and Tensin Homolog (PTEN), inhibiting its phosphatase activity. PTEN is a negative regulator of the PI3K/AKT pathway.16
AKT Activation: With PTEN inhibited, AKT (Protein Kinase B) phosphorylation increases, particularly via mTORC2 signaling.
FOXO1 Exclusion: Activated AKT phosphorylates the transcription factor FOXO1. Phosphorylated FOXO1 is sequestered in the cytoplasm and cannot enter the nucleus. Since nuclear FOXO1 is required to transcribe the Myostatin gene, this sequestration effectively silences myostatin expression.17

This pathway provides the molecular rationale for MOTS-c’s potential in treating sarcopenia and wasting conditions, distinct from its metabolic effects on glucose.

4. Systemic Physiological Effects: Insights from Mammalian Models

4.1 Metabolic Syndrome and Obesity

The administration of MOTS-c in murine models of Diet-Induced Obesity (DIO) has yielded profound metabolic improvements, often comparable to pharmacological interventions like pharmacotherapy or drastic lifestyle changes.

Prevention of Weight Gain: Mice fed a High-Fat Diet (HFD) supplemented with daily MOTS-c injections gained significantly less weight than vehicle-treated controls, despite no difference in caloric intake. This indicates a marked increase in energy expenditure.5
Lipid Partitioning: Histological analysis reveals that MOTS-c prevents lipid droplet accumulation in the liver (hepatic steatosis) and visceral adipose depots.8 Instead, lipid utilization is shifted toward oxidation.
Adipose Tissue Remodeling: MOTS-c promotes the “browning” of white adipose tissue (WAT) and the activation of Brown Adipose Tissue (BAT). It upregulates Thermogenin (UCP1) and other thermogenic genes (e.g., PGC-1α, PRDM16), facilitating the dissipation of energy as heat.9 This thermogenic capacity is a key driver of its anti-obesity effects.
Insulin Sensitization: By promoting GLUT4 translocation to the sarcolemma in skeletal muscle, MOTS-c clears glucose from the bloodstream efficiently. This effect is synergistic with insulin but can occur independently via the AMPK pathway, suggesting utility in states of insulin resistance where canonical insulin signaling is impaired.5

4.2 Skeletal Muscle as the Primary Target

Skeletal muscle is both the primary source (post-exercise) and the primary target of MOTS-c action.

Exercise Mimetic: In treadmill performance tests, mice treated with MOTS-c displayed superior endurance and running capacity compared to controls. This effect persisted across age groups, from young to old mice, leading to the designation of MOTS-c as an “exercise mimetic”.20
Muscle Fiber Type Switching: Chronic exposure to MOTS-c appears to facilitate a shift toward oxidative (Type I) muscle fibers, which are rich in mitochondria and fatigue-resistant, mirroring the adaptations seen in endurance training.22
Prevention of Atrophy: In models of metabolic atrophy (e.g., palmitic acid-induced toxicity), MOTS-c preserved myotube diameter and contractile protein content, validating the myostatin-inhibition mechanism described above.15

4.3 Osteology: A Dual-Action Bone Anabolic

Osteoporosis and osteopenia are often driven by an imbalance between bone-forming osteoblasts and bone-resorbing osteoclasts. MOTS-c appears to rectify this imbalance via the TGF-beta/Smad signaling pathway.

Osteoblastogenesis: It stimulates the proliferation and differentiation of mesenchymal stem cells (MSCs) into osteoblasts, enhancing mineralization and bone matrix synthesis.8
Osteoclastogenesis: Conversely, it inhibits the differentiation of osteoclast precursors, reducing bone resorption rates.
Clinical Implication: In ovariectomized mice (a model for postmenopausal osteoporosis), MOTS-c treatment significantly prevented bone mineral density (BMD) loss.19 This suggests it could serve as a therapeutic for postmenopausal women that addresses both metabolic health and skeletal integrity.

4.4 Cardiovascular Protection

Diabetic cardiomyopathy is characterized by mitochondrial dysfunction, oxidative stress, and fibrosis.

Myocardial Remodeling: In diabetic rats, 8 weeks of MOTS-c treatment repaired mitochondrial ultrastructure in cardiomyocytes and restored systolic/diastolic function.23
Mechanism: Transcriptomic analysis indicated that MOTS-c downregulates CCN1 (Cellular Communication Network Factor 1), which in turn inhibits the ERK1/2 signaling cascade. This reduction in ERK1/2 activation decreases the expression of EGR1, a pro-apoptotic factor, thereby preventing cardiomyocyte death.23
Endothelial Health: MOTS-c also improves endothelial function, likely through AMPK-mediated eNOS (endothelial nitric oxide synthase) activation, reducing vascular inflammation and improving coronary perfusion.19

4.5 Neuroprotection and Traumatic Brain Injury (TBI)

The brain is highly metabolically active and vulnerable to mitochondrial dysfunction.

TBI Recovery: In mouse models of Traumatic Brain Injury, MOTS-c treatment significantly reduced neurological deficits and improved cognitive scores (Morris Water Maze).
Anti-Inflammatory Mechanism: The peptide downregulated Macrophage Migration Inhibitory Factor (MIF) in the brain. MIF is a pro-inflammatory cytokine that drives neuroinflammation; its inhibition by MOTS-c prevented the activation of the RIPK1-dependent necroptosis pathway, preserving neuronal viability.25
Cognitive Decline: MOTS-c also protected against Aβ42-induced memory impairment, suggesting potential relevance for Alzheimer’s disease. However, peripheral administration faces the challenge of the Blood-Brain Barrier (BBB), and high doses or specialized delivery vehicles (e.g., exosomes, intranasal routes) may be required for CNS efficacy.9

4.6 Senescence and Aging

Aging is characterized by the accumulation of senescent cells which secrete pro-inflammatory factors (SASP). MOTS-c levels naturally decline with age in humans and mice.6

Senolytic Potential: Restoring MOTS-c levels in aged mice reduced markers of senescence and SASP in skeletal muscle and circulation.27
Pancreatic Beta-Cells: In models of diabetes, MOTS-c reduced beta-cell senescence, preserving insulin secretion capacity and delaying the onset of hyperglycemia.28

5. Human Clinical Data and The Landscape of Analogs

5.1 Endogenous MOTS-c in Humans

In human populations, circulating MOTS-c levels serve as a biomarker for metabolic health.

Age-Related Decline: Plasma levels are highest in youth and decline progressively with age, correlating with the onset of insulin resistance and endothelial dysfunction.6
Exercise Response: An acute bout of high-intensity cycling in healthy men triggered a 1.5-fold increase in plasma MOTS-c and a nearly 12-fold increase in muscle MOTS-c expression. This elevation persists for hours, mediating the post-exercise metabolic afterburn.20
Obesity: Paradoxically, some studies show lower levels in obese individuals, while others show no correlation or compensatory increases, highlighting the complexity of its regulation in established pathology versus healthy physiology.6

5.2 The Genetic Controversy: m.1382A>C Polymorphism

A specific Single Nucleotide Polymorphism (SNP) in the MT-RNR1 gene, m.1382A>C, results in a Lysine-to-Glutamine substitution (K14Q) in the MOTS-c peptide. This variant is notably prevalent in Northeast Asian populations, including Japanese centenarians.

Initial Hypothesis: Early research suggested this variant might be a “longevity gene.”
Revised Understanding: More rigorous functional assays suggest the K14Q variant may actually be less bioactive than the wild-type peptide. The high levels of circulating MOTS-c observed in carriers may be a compensatory mechanism—the body produces more peptide to overcome its reduced specific activity. This polymorphism is also associated with an increased risk of Type 2 Diabetes in sedentary males, further complicating the picture and emphasizing the interaction between genetics and lifestyle (exercise).5

5.3 Clinical Trials: CB4211 (The Stabilized Analog)

Native peptides have short half-lives in circulation due to rapid enzymatic degradation. Consequently, pharmaceutical development has focused on stabilized analogs. CB4211, a modified MOTS-c analog developed by CohBar, Inc., has advanced to human clinical trials.

Phase 1a/1b Trial (NCT03998514) – Key Findings

This randomized, double-blind, placebo-controlled trial targeted obese subjects with Non-Alcoholic Fatty Liver Disease (NAFLD).30

Cohort: 20 obese subjects with NAFLD (defined as >10% liver fat).
Dosing: 25 mg subcutaneous injection daily for 4 weeks.
Safety Profile: The primary endpoint was met; CB4211 was well-tolerated. The only notable adverse events were mild-to-moderate injection site reactions (erythema, pain), which occurred in >10% of subjects. No serious adverse events (SAEs) or cardiovascular signals were reported.
Biomarker Efficacy:

Liver Enzymes: Subjects receiving CB4211 showed a statistically significant reduction in Alanine Aminotransferase (ALT) by -21% and Aspartate Aminotransferase (AST) by -28% compared to placebo. This is a critical marker of reduced hepatocyte injury.
Glucose Metabolism: Fasting glucose levels dropped by -6%.
Body Weight: A trend toward weight loss was observed, though the study was not powered for this endpoint.
Liver Fat: Both treatment and placebo groups saw reductions in liver fat (approx -5%), likely due to the controlled diet and confinement during the inpatient period, masking the specific drug effect on this metric.

These results provide the first Proof-of-Concept (PoC) in humans that the MOTS-c pathway can be targeted to improve metabolic liver disease and glucose homeostasis.

6. The Oncology Paradox: Tumor Suppression vs. Promotion

The interaction between MOTS-c and cancer is a subject of intense scrutiny and apparent contradiction, necessitated by the peptide’s role in cell growth and metabolism.

6.1 Anti-Tumorigenic Mechanisms (Ovarian Cancer)

In ovarian cancer models, MOTS-c functions as a tumor suppressor.

LARS1 Targeting: Leucyl-tRNA Synthetase 1 (LARS1) is an enzyme often overexpressed in cancer that activates mTORC1 and promotes growth. MOTS-c binds directly to LARS1.
USP7 Competition: The deubiquitinase USP7 normally stabilizes LARS1, preventing its degradation. MOTS-c competes with USP7 for binding to LARS1. By displacing USP7, MOTS-c exposes LARS1 to ubiquitination and subsequent proteasomal degradation.33
Result: This leads to a dramatic reduction in tumor growth and metastasis in vivo, as the cancer cells are deprived of the LARS1-mediated growth signals.

6.2 Pro-Tumorigenic Risks?

Conversely, the “browning” of fat and the systemic increase in glucose uptake induced by MOTS-c could theoretically fuel the high metabolic demands of certain tumors. In Adrenocortical Carcinoma (ACC), MOTS-c expression is lost as the tumor becomes more aggressive, suggesting it normally acts to restrain growth in this tissue.34 However, the FDA has flagged other mitochondrial and growth-hormone-related peptides for potential tumorigenicity in preclinical models.35 Therefore, the use of MOTS-c in the context of active malignancy remains a significant contraindication until tissue-specific effects are fully mapped.

7. Anecdotal Evidence and Gray Market Utilization

Outside the confines of clinical trials, a burgeoning “biohacking” and bodybuilding community has experimented with MOTS-c, providing a repository of observational, albeit uncontrolled, data.

7.1 User Protocols

Unlike the daily administration in trials, gray market users typically adopt pulse protocols 36:

Dosage: 5 mg to 10 mg administered subcutaneously once per week, or 5 mg administered immediately prior to endurance training.
Administration: Injection into abdominal fat or thigh.
Sourcing: “Research chemical” vendors, often with unverified purity.

7.2 Reported Benefits

Endurance: Users consistently report a subjective “third lung” effect—a marked increase in aerobic capacity and delay in the onset of fatigue during high-intensity interval training (HIIT) or cardio.36
Fat Loss: Anecdotal logs frequently cite reductions in visceral adiposity, often accompanied by a sensation of increased body heat (thermogenesis) following injection.

7.3 Reported Side Effects

Injection Site Pain: “MOTS-c burn” is a frequently cited phenomenon. The peptide appears to be irritating to subcutaneous tissue, causing stinging, redness, and localized welts that can last for days.36
Sympathetic Arousal: Users report insomnia, jitters, and heart palpitations if the peptide is taken too late in the day. This aligns with the mechanism of AMPK activation and increased metabolic rate, which can mimic a sympathetic discharge.38
Nausea: A “flu-like” feeling or nausea upon the first few doses is common, potentially related to rapid shifts in blood glucose or hepatic metabolism.36

8. Safety Profile, Immunogenicity, and Contraindications

8.1 The Immunogenicity Trap: Anti-Drug Antibodies (ADAs)

The most significant theoretical risk with exogenous peptide therapy is immunogenicity.

Mechanism: If the immune system identifies the injected MOTS-c as foreign—often due to aggregates formed during improper storage, impurities in gray-market synthesis, or high concentrations—it will generate Anti-Drug Antibodies (ADAs).39
Neutralization Risk: These ADAs can neutralize not only the injected drug but also the patient’s endogenous MOTS-c. This cross-reactivity could precipitate a deficiency syndrome, potentially worsening metabolic health, insulin resistance, or mitochondrial function permanently.40 This “clearing” effect is a well-known risk in biologics (e.g., EPO-induced pure red cell aplasia) and represents a severe danger for unsupervised use.

8.2 Contraindications

Based on current data, the following contraindications are medically prudent:

Active Malignancy: Due to the unknown interactions with various tumor microenvironments and the LARS1 pathway complexity.35
Pregnancy and Lactation: MOTS-c levels regulate placental and fetal metabolism; exogenous disruption could have teratogenic or developmental consequences.42
Hypoglycemia Prone: Patients on insulin or sulfonylureas risk severe hypoglycemia due to the additive glucose-lowering effects of MOTS-c.36

8.3 FDA and Regulatory Stance

The FDA has explicitly placed MOTS-c on the list of substances that cannot be compounded, citing a lack of sufficient safety information and potential risks.35 It is classified as a performance-enhancing drug by WADA (World Anti-Doping Agency) under section S2 (Peptide Hormones, Growth Factors, Related Substances and Mimetics), banning its use in competitive sports.36

9. Theoretical Applications and Future Directions

Bridging the gap between animal models and human potential allows for the extrapolation of theoretical clinical applications.

9.1 Sarcopenic Obesity in the Elderly

The dual ability of MOTS-c to burn fat (via AMPK/BAT) and build muscle (via Myostatin inhibition) makes it the “Holy Grail” candidate for Sarcopenic Obesity—a condition affecting millions of elderly individuals where muscle loss co-exists with fat gain, leading to frailty and metabolic syndrome.43

9.2 The “Exercise Pill” for Rehabilitation

For patients with spinal cord injuries, severe heart failure, or orthopedic limitations that preclude vigorous exercise, MOTS-c could serve as a molecular proxy for physical activity. By activating the same downstream pathways as mechanical load and exertion (mitohormesis), it could prevent the rapid metabolic deterioration associated with immobility.19

9.3 Adjunct to GLP-1 Agonists

The current gold standard for obesity, GLP-1 receptor agonists (e.g., Semaglutide), causes significant weight loss but also results in the loss of lean muscle mass. A theoretical combination of a GLP-1 agonist (for appetite suppression) and MOTS-c (for muscle preservation and metabolic rate enhancement) could represent an optimized pharmacological approach to weight management, ensuring the weight that is lost is primarily adipose tissue.

10. Conclusion

MOTS-c represents a paradigm shift in our comprehension of the mitochondrial genome, transforming it from a static relic to a dynamic endocrine organ. The evidence is compelling: through the unique Folate-AICAR-AMPK axis and nuclear reprogramming, MOTS-c exerts profound effects on glucose metabolism, muscle hypertrophy, and cellular resilience.

The translation of these findings into humans is well underway, with the CB4211 trials providing the first concrete evidence of safety and efficacy in liver disease. However, the path forward is fraught with challenges. The biphasic nature of its effects—beneficial for metabolic disease but potentially risky for specific cancers—along with the specter of immunogenicity, dictates a cautious approach. While the biohacking community races ahead with self-experimentation, the true clinical value of MOTS-c will likely be realized through stabilized, precision-dosed analogs targeting specific pathologies like NASH, sarcopenia, and metabolic frailty.

Table 1: Comparative Analysis of Metabolic Regulators

Feature	MOTS-c	Metformin	Exercise
Primary Target	Folate Cycle / Purine Synthesis	ETC Complex I	Mechanical / ATP depletion
AMPK Activation	Direct (via AICAR accumulation)	Indirect (via ATP/ADP ratio)	Indirect (via ATP/AMP ratio)
Muscle Effect	Hypertrophy (Myostatin inhibition)	Neutral / Slight inhibition	Hypertrophy & Endurance
Bone Effect	Anabolic (Osteoblast stim.)	Neutral	Anabolic (Load dependent)
Nuclear Entry	Yes (translocates to nucleus)	No	No (signals downstream)
Primary Risk	Immunogenicity / Tumor growth	Lactic Acidosis (rare) / GI issues	Injury / Overtraining

Table 2: Summary of Key MOTS-c Signaling Pathways

Pathway	Molecular Target	Physiological Outcome
Metabolic	Folate Cycle > AICAR > AMPK	Insulin sensitization, fatty acid oxidation
Myogenic	CK2 ↑ > PTEN ↓ > AKT ↑ > FOXO1	Myostatin suppression, muscle growth
Thermogenic	UCP1, PGC-1α upregulation	WAT browning, BAT activation
Osteogenic	TGF-β/Smad signaling	Osteoblast differentiation, bone density
Oncogenic	LARS1 binding vs. USP7	Degradation of LARS1, tumor suppression (Ovarian)
Neuroprotective	MIF ↓ > RIPK1 ↓	Reduced neuroinflammation, cognitive protection

This detailed synthesis underscores that MOTS-c is not merely a peptide but a master regulator of the “mitochondrial metabolic code,” offering a glimpse into the future of integrated molecular medicine.