# The Loss of Complex I in Renal Oncocytoma Is Associated with Defective Mitophagy Due to Lysosomal Dysfunction

## TL;DR

This paper shows that loss of mitochondrial Complex I in kidney tumors called renal oncocytoma leads to defective mitophagy due to lysosomal dysfunction.

## Contribution

The study reveals a novel mechanism linking Complex I mutations to impaired mitophagy via lysosomal dysfunction in renal oncocytoma.

## Key findings

- ROs frequently have mtDNA mutations in Complex I genes with high variant allele frequency.
- Complex I loss in ROs leads to reduced Complex I activity and defective lysosome-mediated mitophagy.
- Inhibiting Complex I in normal kidney cells reproduces lysosomal and mitophagy defects seen in ROs.

## Abstract

Renal oncocytoma (RO) is a benign renal neoplasm characterized by dense accumulation of dysfunctional mitochondria possibly resulting from increased mitochondrial biogenesis and decreased mitophagy; however, the mechanisms controlling these mitochondrial changes are unclear. ROs harbor recurrent inactivating mutations in mitochondrial genes encoding the Electron Transport Chain (ETC) Complex I, and we hypothesize that Complex I loss in ROs directly impairs mitophagy. Our analysis of ROs and normal kidney (NK) tissues shows that a significant portion (8 out of 17) of ROs have mtDNA Complex I loss-of-function mutations with high variant allele frequency (>50%). ROs indeed exhibit reduced Complex I expression and activity. Analysis of the various steps of mitophagy pathway demonstrates that AMPK activation in ROs leads to induction of mitochondrial biogenesis, autophagy, and formation of autophagosomes. However, the subsequent steps involving lysosome biogenesis and function are defective, resulting in an overall inhibition of mitophagy. Inhibiting Complex I in a normal kidney cell line recapitulated the observed lysosomal and mitophagy defects. Our data suggest Complex I loss in RO results in defective mitophagy due to lysosomal loss and dysfunction.