Abstract
Mitochondria and peroxisomes are closely related metabolic organelles, both in terms of origin and in terms of function. Mitochondria and peroxisomes can also be turned over by autophagy, in processes termed mitophagy and pexophagy, respectively. However, despite their close relationship, it is not known if both organelles are turned over under similar conditions, and if so, how this might be coordinated molecularly. Here, we find that multiple selective autophagy pathways are activated upon iron chelation and show that mitophagy and pexophagy occur in a BNIP3L/NIX-dependent manner. We reveal that the outer mitochondrial membrane-anchored NIX protein, previously described as a mitophagy receptor, also independently localises to peroxisomes and drives pexophagy. We show this process happens in vivo, with mouse tissue that lacks NIX having a higher peroxisomal content. We further show that pexophagy is stimulated under the same physiological conditions that activate mitophagy, including cardiomyocyte and erythrocyte differentiation. Taken together, our work uncovers a dual role for NIX, not only in mitophagy but also in pexophagy, thus illustrating the interconnection between selective autophagy pathways.
| Original language | English |
|---|---|
| Article number | e111115 |
| Number of pages | 19 |
| Journal | EMBO Journal |
| Volume | 41 |
| Issue number | 24 |
| Early online date | 10 Oct 2022 |
| DOIs | |
| Publication status | E-pub ahead of print - 10 Oct 2022 |
Bibliographical note
Funding Information:We would like to thank the Ganley lab for critical reading of this manuscript and Luke Simpson (MRC-PPU, University of Dundee) for generating the NIX KO clones. We acknowledge Paul Appleton at the Dundee Imaging Facility, Dundee and the Advanced Light Microscopy Service, headed by Ana Oña from CNB, and the technical staff at the animal facility of the CIB Margarita Salas for their support. The Zeiss LSM880 with Airyscan was supported by the “Wellcome Trust Multi-User Equipment Grant” (208401/Z/17/Z). We also acknowledge Prof. Gerald W. Dorn II, Washington University in St. Louis that kindly provided the NIX/BNIP3L tissues. We thank the technical support of the MRC PPU, including the MRC PPU tissue culture team (coordinated by Edwin Allen) and MRC PPU Reagents and Services, especially Thomas Macartney for his help in designing the CRISPR/Cas9 KO cell lines. We also thank Adrien Rousseau, MRC PPU Dundee, for all his help especially for the cloning. We acknowledge the group of prof. Ron Hay, GRE University of Dundee, for the hypoxia incubator. This work was funded by an EMBO Long-Term Fellowship (LPW; ALTF 1077-2018), a grant from the Medical Research Council, UK (IGG; MC_UU_00018/2) and by Ministerio de Ciencia, Innovación y Universidades (MCIU), Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER) PGC2018-098557-B-I00 to PB. JZ-M holds a FPU fellowship from The Ministry of Universities, Spain. AMT was supported in part by the National Institute for Health Research Blood and Transplant Research Unit (NIHR BTRU) in Red Cell Products (IS-BTU-1214-10032), NHSBT R&D funding (WP-15-05), the European Union ITN “EVIDENCE” grant agreement ID 860436. The views expressed are those of the authors and not necessarily those of the National Health Service, NIHR, or the Department of Health and Social Care.
Funding Information:
We would like to thank the Ganley lab for critical reading of this manuscript and Luke Simpson (MRC‐PPU, University of Dundee) for generating the NIX KO clones. We acknowledge Paul Appleton at the Dundee Imaging Facility, Dundee and the Advanced Light Microscopy Service, headed by Ana Oña from CNB, and the technical staff at the animal facility of the CIB Margarita Salas for their support. The Zeiss LSM880 with Airyscan was supported by the “Wellcome Trust Multi‐User Equipment Grant” (208401/Z/17/Z). We also acknowledge Prof. Gerald W. Dorn II, Washington University in St. Louis that kindly provided the NIX/BNIP3L tissues. We thank the technical support of the MRC PPU, including the MRC PPU tissue culture team (coordinated by Edwin Allen) and MRC PPU Reagents and Services, especially Thomas Macartney for his help in designing the CRISPR/Cas9 KO cell lines. We also thank Adrien Rousseau, MRC PPU Dundee, for all his help especially for the cloning. We acknowledge the group of prof. Ron Hay, GRE University of Dundee, for the hypoxia incubator. This work was funded by an EMBO Long‐Term Fellowship (LPW; ALTF 1077‐2018), a grant from the Medical Research Council, UK (IGG; MC_UU_00018/2) and by Ministerio de Ciencia, Innovación y Universidades (MCIU), Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER) PGC2018‐098557‐B‐I00 to PB. JZ‐M holds a FPU fellowship from The Ministry of Universities, Spain. AMT was supported in part by the National Institute for Health Research Blood and Transplant Research Unit (NIHR BTRU) in Red Cell Products (IS‐BTU‐1214‐10032), NHSBT R&D funding (WP‐15‐05), the European Union ITN “EVIDENCE” grant agreement ID 860436. The views expressed are those of the authors and not necessarily those of the National Health Service, NIHR, or the Department of Health and Social Care.
Publisher Copyright:
©2022 The Authors. Published under the terms of the CC BY 4.0 license.
Research Groups and Themes
- Bristol BioDesign Institute