Cellular ATP demand creates metabolically distinct subpopulations of mitochondria
Mitochondria, which synthesize ATP via OXPHOS, are also involved in producing macromolecules like proline and ornithine. However, it remains unclear how both competing metabolic processes occur within the same organelle under bioenergetic stress. The researcher explored how cellular ATP demand creates metabolically distinct mitochondrial subpopulations to balance oxidative phosphorylation (OXPHOS) and reductive biosynthesis.First, the researcher found that increased cellular dependence on OXPHOS triggers the sequestration of pyrroline-5-carboxylate synthase (P5CS), an enzyme critical for proline synthesis, into a subset of mitochondria lacking cristae and ATP synthase. This segregation is regulated by mitochondrial fusion and fission dynamics. Next, experiments disrupting mitochondrial dynamics revealed that failure to separate these distinct metabolic zones compromises either OXPHOS or proline biosynthesis, forcing cells to prioritize one function.Then, the researcher demonstrated that P5CS forms filaments under nutrient stress, clustering into mitochondria without ATP synthase, maintaining reductive biosynthesis independently of ATP production. This mitochondrial subpopulation sustains the biosynthesis of proline and ornithine from glutamate, even when ATP demand is high.In conclusion, the study highlights that mitochondrial fusion and fission enable metabolic compartmentalization, ensuring cells can adapt to nutrient availability and energy demand. The findings underscore the importance of mitochondrial dynamics in maintaining metabolic flexibility, with implications for cell growth, survival, and disease.DOI: 10.1038/s41586-024-08146-w
Ammonia-induced lysosomal and mitochondrial damage causes cell death of effector CD8+ T cells
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Zhang. et al.Nature Cell Biology. 2024
Ammonia, a byproduct of glutaminolysis, is toxic to cells, but its precise role in T cell death was unclear.The researcher investigated how ammonia accumulation causes cell death in effector CD8+ T cells, a distinct process not previously well characterized.
First, the researcher observed that activated CD8+ T cells accumulate ammonia during their clonal expansion phase. Excess ammonia originates from glutaminolysis in mitochondria and is stored in lysosomes. Next, excessive ammonia disrupts lysosomal pH balance, leading to alkalization and the termination of ammonia storage. The reflux of ammonia into mitochondria causes mitochondrial swelling, loss of ATP production, and eventual cell death.Then, experimental inhibition of glutaminolysis using GLS1 inhibitors (such as JHU083 and CB839) reduced ammonia levels, improved lysosomal function, and prevented cell death in vitro and in vivo. Additionally, the overexpression of CPS1, an enzyme involved in ammonia detoxification, mitigated ammonia accumulation and prolonged T cell survival.In summary, this study identifies a novel form of ammonia-induced cell death characterized by lysosomal and mitochondrial damage. These findings reveal ammonia as a key mediator of effector T cell death and highlight potential therapeutic strategies, such as targeting glutaminolysis, to enhance T cell survival in immunotherapy applications.DOI: 10.1038/s41556-024-01503-x
Editor & Reviewer: Congci Yu
