Mitochondria and associated complexes as therapeutic targets in aging: From biomacromolecular structure-function insights to clinical translation.

Abstract

Mitochondria and their biomacromolecular complexes-such as the electron transport chain (ETC), mitochondrial permeability transition pore (mPTP), and protein quality control systems-play pivotal roles in aging and age-related diseases. This review integrates recent insights into how structural and functional disruptions of these complexes drive cellular senescence and systemic decline. We outline the architecture of mitochondrial assemblies (e.g., oxidative phosphorylation (OXPHOS) complexes, mtDNA-protein interactions) essential for energy production and organelle stability. Age-related alterations in stoichiometry, conformational states (e.g., mPTP opening), and post-translational modifications (e.g., SIRT3-mediated acetylation) compromise mitochondrial integrity, fueling metabolic dysfunction and chronic inflammation ("inflammaging"). Therapeutic strategies include small-molecule stabilizers of ETC supercomplexes, peptide-based mPTP inhibitors, and CRISPR-mediated correction of mtDNA-protein mismatches. Tissue-specific models (e.g., Complex I in skin aging, Bcl-2 protein imbalance in ovarian aging) exemplify the clinical relevance. We also categorize nine age-associated diseases-neurodegenerative, cardiovascular, and cancer types-based on their dependence on distinct mitochondrial complexes, such as ATP synthase in cancer resistance and the TIM/TOM import machinery in Alzheimer's disease. By linking structural findings (e.g., cryo-EM studies) with therapeutic innovation, this review offers a framework for targeting mitochondrial complexes to mitigate aging and its related pathologies.