Mitochondria-associated programmed cell death as a therapeutic target for age-related disease

Abstract

Mitochondria, ubiquitous double-membrane-bound organelles, regulate energy production, support cellular activities, harbor metabolic pathways, and, paradoxically, mediate cell fate. Evidence has shown mitochondria as points of convergence for diverse cell death-inducing pathways that trigger the various mechanisms underlying apoptotic and nonapoptotic programmed cell death. Thus, dysfunctional cellular pathways eventually lead or contribute to various age-related diseases, such as neurodegenerative, cardiovascular and metabolic diseases. Thus, mitochondrion-associated programmed cell death-based treatments show great therapeutic potential, providing novel insights in clinical trials. This review discusses mitochondrial quality control networks with activity triggered by stimuli and that maintain cellular homeostasis via mitohormesis, the mitochondrial unfolded protein response, and mitophagy. The review also presents details on various forms of mitochondria-associated programmed cell death, including apoptosis, necroptosis, ferroptosis, pyroptosis, parthanatos, and paraptosis, and highlights their involvement in age-related disease pathogenesis, collectively suggesting therapeutic directions for further research.

Age-related disease: Role of compromised control of mitochondrial quality

Therapies directed at the quality control systems of mitochondria have the potential to preserve cellular health in individuals with age-related diseases. Dongryeol Ryu from Gwangju Institute of Science and Technology in South Korea, Riekelt Houtkooper from the Amsterdam University Medical Center in The Netherlands, and colleagues review how dysfunctional mitochondria, which are responsible for producing energy in cells, contribute to cancer and many neurodegenerative, cardiovascular and metabolic conditions. When mitochondria become damaged or stressed, they can trigger cell death mechanisms via impaired quality-control networks and associated signaling pathways, further exacerbating disease processes. By gaining a deeper understanding of how mitochondrial safeguards help to maintain functional integrity, and the different ways in which mitochondria-associated cell death occurs, researchers may identify new targets for drug development.