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Review
. 2022 May 2;132(9):e158449.
doi: 10.1172/JCI158449.

Mitochondria-derived peptides in aging and healthspan

Brendan Miller, Su-Jeong Kim, Hiroshi Kumagai, Kelvin Yen, Pinchas Cohen
Review

Mitochondria-derived peptides in aging and healthspan

Brendan Miller et al. J Clin Invest. .

Abstract

The mechanisms that explain mitochondrial dysfunction in aging and healthspan continue to be studied, but one element has been unexplored: microproteins. Small open reading frames in circular mitochondria DNA can encode multiple microproteins, called mitochondria-derived peptides (MDPs). Currently, eight MDPs have been published: humanin, MOTS-c, and SHLPs 1-6. This Review describes recent advances in microprotein discovery with a focus on MDPs. It discusses what is currently known about MDPs in aging and how this new understanding could add to the way we understand age-related diseases including type 2 diabetes, cancer, and neurodegenerative diseases at the genomic, proteomic, and drug-development levels.

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Conflict of interest statement

Conflict of interest: PC is an advisor to and stockholder in CohBar Inc. UCLA has licensed the intellectual property on humanin, MOTS-c, and SHLPs, on which PC is listed as an inventor, to CohBar.

Figures

Figure 1
Figure 1. Overview of mitochondria-derived peptides.
Mitochondria contain DNA with small open reading frames (sORFs) that encode functional microproteins, called mitochondria-derived peptides (MDPs). These MDPs can stay inside mitochondria, enter the cytosol, translocate to the nucleus, or be secreted extracellularly to target tissues.
Figure 2
Figure 2. Mitochondria-derived peptides in age-related disease.
Three MDPs have been studied in the context of age-related diseases: humanin, MOTS-c, and SHLP2. Humanin has been shown to mitigate Alzheimer’s disease pathology in rodents, and its levels and genetic variation associate with age and cognition. MOTS-c has been described as an exercise mimetic and prevents muscle atrophy in mice, and its levels and genetic variation associate with age and type 2 diabetes (T2D). SHLP2 functions as a mitochondrial modulator and protein chaperone, and its levels associate with age and prostate cancer.
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