Cellular Metabolism

Cellular metabolism comprises the processes involved in the storage and expenditure of energy, and it plays a critical role in determining the fate and function of cells. ^{[1] [2]} Mitochondria are central hubs of cellular metabolism, maintaining cellular bioenergetics through the production of ATP by oxidative phosphorylation while also contributing to the synthesis of metabolic precursors, calcium regulation, reactive oxygen species production, immune signaling and apoptosis. ^[3] Beyond simply supplying the substrates for biological processes, metabolites also provide critical signals through effects on metabolic pathways or via modulation of other regulatory proteins. ^[4]

Cells undergo metabolic reprogramming as a compensatory mechanism to fulfill the energy needs required for survival and growth. ^[5] Upon activation, T cells undergo rapid metabolic reprogramming characterized by an elevation in both glycolysis and oxidative phosphorylation, with the balance shifting predominantly towards glycolysis to enable rapid proliferation. ^[2] In microglia, metabolism adapts to environmental stimuli by shifting between oxidative phosphorylation and glycolysis, with AMPK acting as an energy sensor that coordinates lipid and glucose metabolism. ^[6] Lysosome-mediated signalling pathways and transcription programmes sense the status of cellular metabolism and control the switch between anabolism and catabolism by regulating lysosomal biogenesis and autophagy. ^[7] Redox reactions are intrinsically linked to energy metabolism, and reactive oxygen species produced during normal aerobic metabolism can reversibly oxidize redox-sensitive cysteine residues to mediate redox signaling and regulate cellular functions. ^[8]

Deregulated nutrient-sensing is a hallmark of aging, and the equivalence or antagonism between aging-associated deregulated nutrient-sensing and cancer-relevant alterations of cellular metabolism is complex. ^[9] On average, aging is associated with unfavorable changes in cellular metabolism, and those who age rapidly are at increased risk of adverse health outcomes and are said to be frail. ^[1] Cellular metabolism plays a significant role in the regulation of the signaling processes involved in cellular senescence, and both senescence and the senescence-associated secretory phenotype are sensitive to cellular and organismal metabolic states. ^{[10] [11]} Mitochondrial dysfunction can represent a harbinger of disease, and translational medicine has begun to investigate how such dysfunction is associated with disease pathogenesis and aging. ^[3]

Metabolic interventions that can mitigate the degree of frailty in people have been reviewed, and maintaining a youthful metabolism into older age is suggested to be protective against frailty. ^[1] The most effective interventions are expected to break a degenerative feedback cycle by which cellular senescence promotes metabolic diseases, which in turn promote senescence. ^[11] Because reprogrammed metabolism is a hallmark of cancer, it is possible to target cancers metabolically, and metabolic pathways are regarded as attractive therapeutic targets in disease. ^[12] Mitochondria-dependent pathways may represent an attractive therapeutic target for ameliorating human disease. ^[3]