Oxidative Insults and Mitochondrial DNA Mutation Promote Enhanced Autophagy and Mitophagy Compromising Cell Viability in Pluripotent Cell Model of Mitochondrial Disease

Abstract

Dysfunction of mitochondria causes defects in oxidative phosphorylation system (OXPHOS) and increased production of reactive oxygen species (ROS) triggering the activation of the cell death pathway that underlies the pathogenesis of aging and various diseases. The process of autophagy to degrade damaged cytoplasmic components as well as dysfunctional mitochondria is essential for ensuring cell survival. We analyzed the role of autophagy inpatient-specific induced pluripotent stem (iPS) cells generated from fibroblasts of patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) with well-characterized mitochondrial DNA mutations and distinct OXPHOS defects. MELAS iPS cells recapitulated the pathogenesis of MELAS syndrome, and showed an increase of autophagy in comparison with its isogenic normal counterpart, whereas mitophagy is very scarce at the basal condition. Our results indicated that the existence of pathogenic mtDNA alone in mitochondrial disease was not sufficient to elicit the degradation of dysfunctional mitochondria. Nonetheless, oxidative insults induced bulk macroautophagy with the accumulation of autophagosomes and autolysosomes upon marked elevation of ROS, overload of intracellular calcium, and robust depolarization of mitochondrial membrane potential, while mitochondria respiratory function was impaired and widespread mitophagy compromised cell viability. Collectively, our studies provide insights into the dysfunction of autophagy and activation of mitophagy contributing to the pathological mechanism of mitochondrial disease.

Baicalein Attenuates Pyroptosis and Endoplasmic Reticulum Stress Following Spinal Cord Ischemia-Reperfusion Injury via Autophagy Enhancement

“…The interactions and relationships among autophagy, pyroptosis and ERS-mediated apoptosis have been widely studied, as Li et al have reported that autophagy protected HUVECs against ER stress-mediated apoptosis (Li et al, 2019). Increasing evidence demonstrates that hypoxic/ ischemic conditions lead to mitochondrial injury (Zuo et al, 2014) and that damaged mitochondria lead to a massive accumulation of ROS (Lin et al, 2019a). Studies have clarified that the massive accumulation of ROS can induce the NLRP3 inflammasome and subsequently trigger caspase-1-dependent pyroptosis (Qiu et al, 2017).…”

Betulinic Acid Inhibits ROS-Mediated Pyroptosis in Spinal Cord Injury by Augmenting Autophagy via the AMPK-mTOR-TFEB Signaling Pathway

“…Increasing evidence demonstrates that the secondary injury stage after SCI is closely related to mitochondrial injury and excessive ROS generation [54]. Damaged mitochondria leads to a massive accumulation of ROS, which can induce NLRP3 in ammasome activation and subsequently trigger caspase-1-dependent pyroptosis [55,56]. Mitophagy, a selective autophagic degradation of damaged mitochondria [57], can reduce ROS accumulation [58,59], and may play a central role in curtailing pyroptosis following SCI.…”

The Mitochondrial Permeability Transition: Nexus of Aging, Disease and Longevity

“…Dopaminergic neurons are more susceptible to mPTP activation than other cells because they are particularly common in aging, causing the overactivation of mPTP, thereby leading to cell death [ 237 ]. The overactivation of autophagy/mitophagy is a major factor in a variety of other neurodegenerative diseases [ 238 ].…”