Abstract
Because injured mitochondria can accelerate cell death through the elaboration of oxidative free radicals and other mediators, it is striking that proliferator γ coactivator 1-α (PGC1α), a stimulator of increased mitochondrial abundance, protects stressed renal cells instead of potentiating injury. Here, we report that PGC1α’s induction of lysosomes via transcription factor EB (TFEB) may be pivotal for kidney protection. CRISPR and stable gene transfer showed that PGC1α-KO tubular cells were sensitized to the genotoxic stressor cisplatin, whereas Tg cells were protected. The biosensor mitochondrial-targeted Keima (mtKeima) unexpectedly revealed that cisplatin blunts mitophagy both in cells and mice. PGC1α and its downstream mediator NAD+ counteracted this effect. PGC1α did not consistently affect known autophagy pathways modulated by cisplatin. Instead RNA sequencing identified coordinated regulation of lysosomal biogenesis via TFEB. This effector pathway was sufficiently important that inhibition of TFEB or lysosomes unveiled a striking harmful effect of excess PGC1α in cells and conditional mice. These results uncover an unexpected effect of cisplatin on mitophagy and PGC1α’s reliance on lysosomes for kidney protection. Finally, the data illuminate TFEB as a potentially novel target for renal tubular stress resistance.
Highlights
Mitochondria are critical for normal kidney function, evidenced by the high penetrance of tubulopathy among people with monogenic mitochondrial diseases [1]
After completing concentration-ranging studies in cells (Supplemental Figure 4A), we found that KO cells produced baseline less ATP at baseline and suffered greater ATP depletion following cisplatin than control cells (Figure 1, C and D)
Cisplatin-mediated injury to tubules was quantified by the expression of kidney injury molecule-1 (KIM1) in renal homogenates from these experiments (Supplemental Figure 5)
Summary
Mitochondria are critical for normal kidney function, evidenced by the high penetrance of tubulopathy among people with monogenic mitochondrial diseases [1]. While mitochondria enable life-sustaining functions, they accelerate cell death when stressed. From this perspective, increased mitochondrial abundance prior to injury should favor cell death rather than cell protection. We recently found that tubular induction of the mitochondrial biogenesis factor peroxisome proliferator γ coactivator 1-α (PGC1α) increased mitochondrial mass and protected from ischemic and inflammatory renal injury [6]. PGC1α limits the damage that can arise from mitochondrial oxidants by inducing antioxidant enzymes [8]. Renal tubular PGC1α does not induce such enzymes [6], leaving unaddressed how mitochondrial biogenesis and mitochondrially targeted antioxidants can both be beneficial in the same models of acute kidney injury (AKI)
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