Mitochondrial Function

Mitochondria are dynamic organelles essential for cellular energy generation, including through oxidative phosphorylation, alongside metabolic regulation and signal transduction. ^{[1] [2]} Beyond energy production, mitochondria are integral to the synthesis of metabolic precursors, calcium regulation, the production of reactive oxygen species, immune signalling and apoptosis. ^[2]

Mitochondrial function is shaped by dynamic morphology, as conserved genes controlling mitochondrial fusion and fission regulate mitochondrial shape and ultrastructure, which in turn control mitochondrial function. ^[3] Mitochondrial dysfunction can be operationally defined as a decreased respiratory capacity per mitochondrion together with a decreased mitochondrial membrane potential, typically accompanied by increased production of oxygen free radicals. ^[4] Cells sense impaired mitochondrial integrity and activate a transcriptional response known as the mitochondrial unfolded protein response, which promotes cell survival and recovery of the mitochondrial network. ^[5]

Mitochondrial dysfunction is one of the recognized hallmarks of aging. ^{[6] [7]} Mitochondrial function declines during ageing owing to the accumulation of deleterious mitochondrial genomes and damage from the localized generation of reactive oxygen species. ^[5] Mitochondrial dysfunction is both a cause and a consequence of cellular senescence and figures prominently in feedback loops that induce and maintain the senescent phenotype. ^[4]

Mitochondrial dysfunction contributes to the pathology of many common disorders including neurodegeneration, metabolic disease, heart failure and ischaemia-reperfusion injury, making mitochondria an important drug target. ^[8] Several strategies aimed at therapeutically restoring mitochondrial function are emerging, and a small number of agents have entered clinical trials. ^[8] Senescence-associated mitochondrial dysfunction has been proposed as an antiaging and antisenescence intervention target, with combinations of interventions converging on it explored as potential senolytics. ^[4]