TFEB-driven lysosomal biogenesis is pivotal for PGC1α-dependent renal stress resistance

• DOI: 10.1172/jci.insight.126749
• Publication Date: 2019-03-14T16:08:20Z
• Authors: Matthew R. Lynch; Mei T. Tran; Kenneth M. Ralto; Zsuzsanna K. Zsen...; 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
• Keywords: TFEB

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 increased mitochondrial abundance, protects stressed renal cells instead potentiating injury. Here, we report PGC1α's induction lysosomes via transcription factor EB (TFEB) may be pivotal for kidney protection. CRISPR stable gene transfer showed PGC1α-KO tubular were sensitized to genotoxic stressor cisplatin, whereas Tg protected. The biosensor mitochondrial-targeted Keima (mtKeima) unexpectedly revealed cisplatin blunts mitophagy both in mice. PGC1α its downstream mediator NAD+ counteracted this effect. did not consistently affect known autophagy pathways modulated by cisplatin. Instead RNA sequencing identified coordinated regulation lysosomal biogenesis TFEB. This effector pathway was sufficiently important inhibition TFEB or unveiled harmful effect excess conditional These results uncover an unexpected on reliance Finally, data illuminate as potentially novel target stress resistance.