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More than 800 million people suffer from kidney disease. Genetic studies and follow-up animal models and cell biological experiments indicate the key role of proximal tubule metabolism. Kidneys have one of the highest mitochondrial densities. Mitochondrial biogenesis, mitochondrial fusion and fission, and mitochondrial recycling, such as mitophagy are critical for proper mitochondrial function. Mitochondrial dysfunction can lead to an energetic crisis, orchestrate different types of cell death (apoptosis, necroptosis, pyroptosis, and ferroptosis), and influence cellular calcium levels and redox status. Collectively, mitochondrial defects in renal tubules contribute to epithelial atrophy, inflammation, or cell death, orchestrating kidney disease development.