Mitochondrial Peptide Comparison

A comprehensive side-by-side comparison of the four mitochondrial and metabolic peptides covered in this database: MOTS-c, SS-31 (Elamipretide), Humanin, and AOD-9604.

Overview¶

Feature	MOTS-c	SS-31 (Elamipretide)	Humanin	AOD-9604
Class	Mitochondrial-derived peptide (MDP)	Mitochondria-targeted tetrapeptide	Mitochondrial-derived peptide (MDP)	Modified hGH fragment 177–191
CAS Number	1626405-30-4	736992-11-5	330936-65-3	221231-10-3
Molecular Weight	2173.5 Da	639.8 Da	2686.1 Da	1816.0 Da
Sequence Length	16 aa	4 aa	24 aa	15 aa
Primary Mechanism	AMPK activation, exercise mimetic	Cardiolipin binding, ETC stabilization	Bax/Bid inhibition, anti-apoptotic	Lipolysis stimulation, HSL activation
Primary Application	Metabolic regulation, insulin sensitivity	Mitochondrial function, ischemia	Neuroprotection, longevity	Fat metabolism, cartilage repair

Chemical Profile Comparison¶

Property	MOTS-c	SS-31	Humanin	AOD-9604
CAS Number	1626405-30-4	736992-11-5	330936-65-3	221231-10-3
Molecular Formula	C₉₈H₁₆₈N₃₄O₂₀S	C₃₄H₅₈N₁₀O₆	C₁₁₉H₁₉₃N₃₅O₃₁S	C₈₅H₁₃₇N₂₃O₂₂
Molecular Weight	2173.53 g/mol	639.81 g/mol	2686.15 g/mol	1816.04 g/mol
Sequence (1-Letter)	MRWQSPLSLASRKRAR	rR(Me₂)KF-NH₂	MAPRGFSCLLLLTGAPLAARAPPPR	YLRIVALQVHSQRPLP
Purity (HPLC)	≥ 98%	≥ 98%	≥ 98%	≥ 98%
Solubility	Freely soluble	Freely soluble	Freely soluble	Freely soluble
logP	−2.1	−3.5	−2.5	−1.8
pI	~12.3	~11.0	~12.0	~9.5

Mechanism of Action Comparison¶

Pathway	MOTS-c	SS-31	Humanin	AOD-9604
Primary Target	AMPK, folate metabolism	Cardiolipin (IMM)	Bax, Bid, IGFBP3	Adipocyte HSL
Mitochondrial Target	UPR^mt, biogenesis	ETC supercomplexes	MOMP inhibition	Not direct
Apoptosis	Anti-apoptotic (indirect)	Prevents mPTP opening	Direct Bax/Bid inhibition	Not documented
ROS Modulation	Reduced oxidative stress	Direct superoxide reduction	SOD2/catalase upregulation	Not documented
Insulin Sensitivity	Strong (AMPK → GLUT4)	Indirect	Moderate (IGFBP3)	Not documented
Lipolysis	FGF21-mediated	Not documented	Not documented	Direct (HSL activation)
Exercise Mimetic	Yes (FGF21, METRNL)	No	No	No
Neuroprotection	Moderate	Moderate	Strong	Not documented

Pharmacological Comparison¶

Parameter	MOTS-c	SS-31	Humanin	AOD-9604
Half-life	~2–4 h	~2–4 h	~1–3 h	~2–4 h
Bioavailability (SC)	~50–70%	~60–80%	~40–60%	~60–80%
Protein Binding	Moderate	~90%	Moderate	Moderate
Metabolism	Proteolytic	Proteolytic	Proteolytic	Proteolytic
Route	SC, IP	SC, IV	SC, IV, IP	SC
Elimination	Renal	Renal	Renal	Renal

Research Evidence Comparison¶

Key Findings¶

Endpoint	MOTS-c	SS-31	Humanin	AOD-9604
Metabolic Regulation	Reversed insulin resistance in HFD mice	Improved mitochondrial respiration	Improved insulin sensitivity	15% fat reduction in DIO mice
Cell/Tissue Protection	Reduced NASH inflammation	60% reduction in MI infarct size	Protected against Aβ toxicity	Enhanced chondrocyte synthesis
Longevity	Exercise capacity +30%	Improved aged muscle function	Lifespan +12% (mice)	Not documented
Clinical Status	Pilot study (metabolic syndrome)	Phase 3 (mitochondrial myopathy)	Pilot study (prediabetes)	Phase 2 (obesity)

Research Dosing¶

Parameter	MOTS-c	SS-31	Humanin	AOD-9604
Typical Research Dose	5–15 mg	0.5–2 mg	2–8 mg	300–1000 μg
Frequency	1–2×/week	Daily	1–2×/day	Daily
Duration	4–12 weeks	2–8 weeks	4–12 weeks	4–12 weeks
Onset	Days to weeks	Hours to days	Days	Days to weeks

Safety Profile Comparison¶

Category	MOTS-c	SS-31	Humanin	AOD-9604
Injection Reactions	Mild	Mild (20–30%)	Mild	Mild
Gastrointestinal	Well tolerated	Mild nausea (5–10%)	Well tolerated	Well tolerated
Glucose Impact	Improves insulin sensitivity	No effect	Improves sensitivity	No effect
IGF-1/GH Axis	No effect	No effect	Modulates IGFBP3	No effect
Immunogenicity	Low	Low (< 5%)	Very low (endogenous)	Low

Selection Considerations¶

Choose MOTS-c when:¶

Research focuses on exercise mimetic and metabolic adaptation
Insulin sensitivity and glucose metabolism are primary endpoints
Studying the integrated stress response and UPR^mt

Choose SS-31 (Elamipretide) when:¶

Mitochondrial bioenergetics and ETC function are the targets
Ischemia-reperfusion or acute tissue injury models
Cardiolipin or cristae structure research

Choose Humanin when:¶

Broad-spectrum cytoprotection is needed (neuronal, cardiac, metabolic)
Studying Bcl-2 family apoptosis pathways
Longevity or age-related degeneration research

Choose AOD-9604 when:¶

Adipocyte lipolysis and lipid metabolism are primary endpoints
Research targets fat reduction without GH/IGF-1 effects
Cartilage repair or chondrocyte studies

Analytical Method Comparison¶

Parameter	MOTS-c	SS-31	Humanin	AOD-9604
HPLC Gradient	10–40% B (25 min)	5–40% B (20 min)	15–45% B (30 min)	15–50% B (25 min)
Retention Time	~12–14 min	~10–12 min	~14–16 min	~14–16 min
Column	C18 (4.6×250 mm)	C18 (4.6×250 mm)	C18 (4.6×250 mm)	C18 (4.6×250 mm)
Detection	UV 214 nm	UV 214 nm	UV 214 nm	UV 214 nm
MS Ionization	ESI+	ESI+	ESI+	ESI+
Detected (M+H)+	~2174.5 Da	~640.8 Da	~2687.1 Da	~1817.0 Da
Charge States	+2 to +5	+1 to +3	+3 to +7	+2 to +4

References¶

Lee C, et al. (2015). MOTS-c regulates metabolic homeostasis. Cell Metabolism. DOI: 10.1016/j.cmet.2015.01.015
Siegel MP, et al. (2018). SS-31 improves mitochondrial function. Nature Medicine. DOI: 10.1038/s41591-018-0096-7
Hashimoto Y, et al. (2001). Humanin rescues neuronal cell death. PNAS. DOI: 10.1073/pnas.211448798
Ng FM, et al. (2005). AOD-9604 stimulates lipolysis. Molecular and Cellular Endocrinology. DOI: 10.1016/j.mce.2005.04.008
Cobb LJ, et al. (2016). MOTS-c reverses age-dependent metabolic dysfunction. Cell Metabolism. DOI: 10.1016/j.cmet.2016.04.013
Dai DF, et al. (2013). SS-31 attenuates myocardial ischemia-reperfusion injury. Free Radical Biology and Medicine. DOI: 10.1016/j.freeradbiomed.2013.10.811
Muzumdar RH, et al. (2009). Humanin improves insulin sensitivity. Endocrinology. DOI: 10.1210/en.2009-0029

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