Review examining mitochondrial-derived microproteins (MOTS-c, humanin, SHLPs, SHMOOSE) as cross-disease regulators of aging, metabolism, cancer biology, and neurodegeneration, analyzing how MDP-mediated pathways including apoptosis, nutrient sensing, and mito-nuclear communication may explain the inverse comorbidity between cancer and Alzheimer's disease. Provides a unifying mechanistic framework. Offers a novel cross-disease perspective on MOTS-c—establishing that MDP signaling pathways operate across neurodegeneration and oncology in ways that may inform why Alzheimer's disease and cancer rarely co-occur, with implications for aging research and drug development.
Abstract
Mitochondrial-derived microproteins (MDPs) translate mitochondrial stress into cellular decisions that shape aging, metabolism, cancer biology, and neurodegeneration. Humanin, MOTS-c, SHLPs, and the recently identified SHMOOSE act through distinct intracellular and receptor-mediated pathways to regulate apoptosis, nutrient sensing, redox balance, and mito-nuclear communication. These programs confer neuroprotection in post-mitotic tissues but can be co-opted by tumors for survival, invasion, and therapy resistance, helping explain the inverse comorbidity between cancer and Alzheimer's disease. This review synthesizes the divergent signaling architectures of major MDPs, including Humanin-FPR2/gp130, MOTS-c-AMPK/NRF2-LARS1/mTORC1, SHLP2-CXCR7, and SHMOOSE's genotype-dependent activity, and outlines how these mechanisms produce disease-specific outcomes. Recent advances in mitoribosome profiling, DIA-based proteogenomics, and mitochondrial base editing have accelerated the discovery and functional characterization of MDPs. Emerging translational opportunities include MDP-targeted agonists, antagonists, and engineered delivery systems designed for application in neurodegenerative disorders and cancer. Overall, MDPs represent a druggable signaling layer whose context-dependent effects can be selectively directed across diseases.