Acute and chronic mitochondrial respiratory chain deficiency differentially regulate lysosomal biogenesis

Lorena Fernández-Mosquera,Cátia V. Diogo,King Faisal Yambire,Luis Carlos Lopez,Marta Luna Sánchez,Ira Milosevic,Pierre Rustin,Nuno Raimundo,Gabriela L. Santos,Paule Bénit

doi:10.1038/srep45076

Abstract

Mitochondria are key cellular signaling platforms, affecting fundamental processes such as cell proliferation, differentiation and death. However, it remains unclear how mitochondrial signaling affects other organelles, particularly lysosomes. Here, we demonstrate that mitochondrial respiratory chain (RC) impairments elicit a stress signaling pathway that regulates lysosomal biogenesis via the microphtalmia transcription factor family. Interestingly, the effect of mitochondrial stress over lysosomal biogenesis depends on the timeframe of the stress elicited: while RC inhibition with rotenone or uncoupling with CCCP initially triggers lysosomal biogenesis, the effect peaks after few hours and returns to baseline. Long-term RC inhibition by long-term treatment with rotenone, or patient mutations in fibroblasts and in a mouse model result in repression of lysosomal biogenesis. The induction of lysosomal biogenesis by short-term mitochondrial stress is dependent on TFEB and MITF, requires AMPK signaling and is independent of calcineurin signaling. These results reveal an integrated view of how mitochondrial signaling affects lysosomes, which is essential to fully comprehend the consequences of mitochondrial malfunction, particularly in the context of mitochondrial diseases.

Highlights

From the lysosomes, resulting in the activation of calcineurin which can dephosphorylate TFEB and related molecules[13]
The effects of rotenone and Carbonyl cyanide 3-chlorophenylhydrazone (CCCP) on the overall activity of the respiratory chain, as measured by O2 consumption, show that the treatments are working as expected (Supplementary Figure 1B). These results show that the effect of acute and chronic mitochondrial respiratory chain deficiency in lysosomal biogenesis may be different
This study addresses the mechanisms by which mitochondrial malfunction, and respiratory chain deficiency, impact lysosomal biogenesis

Summary

Introduction

From the lysosomes, resulting in the activation of calcineurin which can dephosphorylate TFEB and related molecules[13]. Dephosphorylated TFEB can relocate to the nucleus and drive its transcriptional program. Lysosomes become dysfunctional and TFEB relocates to the nucleus[14,15,16]. The mechanisms linking these processes remain not completely understood[7]. We show how acute and chronic respiratory chain defects have opposite effects on lysosomal biogenesis, both in cultured cells and in vivo in a mouse model of respiratory chain dysfunction. While acute mitochondrial stress triggers a AMPK-TFEB/MITF pathway that leads to increased lysosomal biogenesis, chronic mitochondrial stress results in repression of lysosomal biogenesis

Methods

Results

Conclusion