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.

The pyroptosis mediated biomarker pattern: an emerging diagnostic approach for Parkinson’s disease

“…However, the functional significance of the neuronal capsase-3/GSDME signalling pathway in the CNS remains a mystery. Recent studies have shown that higher levels of GSDME play a significant role in the progression of neurodegenerative diseases by translocating into neuronal mitochondria to cause mitochondrial depolarization and neuronal damage [ 75 , 76 ]. Studies on ischemia–reperfusion have shown that elevated lncH19 expression would significantly boost NLRP3/6 inflammasome imbalance, causing pyroptosis in the microglia and neurons [ 77 ].…”

Evaluation of histological and ultrastructural changes provoked by prenatal tramadol on postnatal cortical cerebellar neuronal development in rats: possible implication of Ki67, GFAP and MicroRNA-7/P53 signalling trajectories

“…Tramadol-treated groups exhibited notable mitochondrial alterations, including an abundance of vacuolated and enlarged mitochondria within degenerated neurons. Oxidative stress-induced disruption of mitochondrial cristae is widely recognized to result in a reduction in energy production and the initiation of DNA fragmentation (Nguyen et al 2023 ). Similar mitochondrial alterations have been observed in the brains of tramadol-treated rats in earlier studies (Omar 2016 ) and these alterations were stopped by antioxidant therapy.…”

VDR restores the expression of PINK1 and BNIP3 in TECs of streptozotocin-induced diabetic mice

“…Although the functions of PINK1 and BNIP3 have been widely recognized for their abilities to mediate mitophagy (25), whether they are directly involved in the regulation of VDR on mitophagy and fibrosis in diabetic conditions is unknown. Therefore, we transfected PINK1 siRNAs or BNIP3 siRNAs to knock down the expression of PINK1 or BNIP3 in HK-2 cells (Fig 7A and B).…”