First published August 6, 2020 - More info
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.
Matthew R. Lynch, Mei T. Tran, Kenneth M. Ralto, Zsuzsanna K. Zsengeller, Vinod Raman, Swati S. Bhasin, Nuo Sun, Xiuying Chen, Daniel Brown, Ilsa I. Rovira, Kensei Taguchi, Craig R. Brooks, Isaac E. Stillman, Manoj K. Bhasin, Toren Finkel, Samir M. Parikh
Original citation: JCI Insight. 2019;4(8):e126749. https://doi.org/10.1172/jci.insight.126749
Citation for this erratum: JCI Insight. 2020;5(15):e142898. https://doi.org/10.1172/jci.insight.142898
When the article was originally published, an incorrect panel was included in Figure 5E. The correct figure part is below. The HTML and PDF files have been updated online.
JCI Insight regrets the error.
See the related article at TFEB-driven lysosomal biogenesis is pivotal for PGC1α-dependent renal stress resistance.