Hypoxia-induced mitochondrial stress granules

Abstract

Perturbations of mitochondrial proteostasis have been associated with aging, neurodegenerative diseases, and recently with hypoxic injury. While examining hypoxia-induced mitochondrial protein aggregation in C. elegans, we found that sublethal hypoxia, sodium azide, or heat shock-induced abundant ethidium bromide staining mitochondrial granules that preceded evidence of protein aggregation. Genetic manipulations that reduce cellular and organismal hypoxic death block the formation of these mitochondrial stress granules (mitoSG). Knockdown of mitochondrial nucleoid proteins also blocked the formation of mitoSG by a mechanism distinct from the mitochondrial unfolded protein response. Lack of the major mitochondrial matrix protease LONP-1 resulted in the constitutive formation of mitoSG without external stress. Ethidium bromide-staining RNA-containing mitochondrial granules were also observed in rat cardiomyocytes treated with sodium azide, a hypoxia mimetic. Mitochondrial stress granules are an early mitochondrial pathology controlled by LONP and the nucleoid, preceding hypoxia-induced protein aggregation.

Mitochondrial p38 Mitogen-Activated Protein Kinase: Insights into Its Regulation of and Role in LONP1-Deficient Nematodes

“…These include UPR mt , where increased activity of the ATFS-1 transcription factor was found to be essential for normal development of lonp-1 mutants and determines the resistance of lonp-1 adults to external oxidative stress [30]. Interestingly, lack of LONP-1 was recently reported to induce constitutive formation of mitochondrial stress granules, perhaps as an adaptive response [56]. Moreover, ATFS-1 activity in longlived isp-1 mitochondrial mutants could prevent the induction of another mitochondrial stress signaling pathway named MAPK mt , in which PMK-3/p38 MAPK upregulates the expression of the tbb-6 beta-tubulin target gene in the intestines [24].…”

Protein aggregation and biomolecular condensation in hypoxic environments (Review)

“…It is noteworthy that nematodes and rat cardiomyocytes produced characteristic SGs in mitochondria stimulated by sublethal hypoxia. Mitochondrial SGs are involved in early mitochondrial pathology and are closely associated with UPRmt ( 14 ).…”

“…This imbalance can also activate the assembly of biomolecular condensates, which play crucial roles as organelles without membrane and are regulated by multiple mechanisms related to environmental stress ( 3 ). Stress granules (SGs) ( 14 ), glycolytic bodies (G-bodies) ( 15 ) and processing bodies (P-bodies) ( 16 ) contribute to cell survival under stress conditions and induce metabolic reprogramming in hypoxic environments.…”