PINK1 deficiency alters muscle stem cell fate decision and muscle regenerative capacity

George Cairns; Madhavee Thumiah-Mootoo; Mah Rukh Abbasi; Melissa Gourlay; Jeremy Racine; Nikita Larionov; Alexandre Prola; Mireille Khacho; Yan Burelle

doi:10.1016/j.stemcr.2024.03.004

PINK1 deficiency alters muscle stem cell fate decision and muscle regenerative capacity

Stem Cell Reports. 2024 Mar 26:S2213-6711(24)00079-1. doi: 10.1016/j.stemcr.2024.03.004. Online ahead of print.

Authors

George Cairns¹, Madhavee Thumiah-Mootoo², Mah Rukh Abbasi², Melissa Gourlay², Jeremy Racine², Nikita Larionov², Alexandre Prola³, Mireille Khacho⁴, Yan Burelle⁵

Affiliations

¹ Interdisciplinary School of Health Sciences, Faculty of Health Sciences, University of Ottawa, Ottawa, ON, Canada.
² Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada.
³ Department of Cell Physiology and Metabolism, University of Geneva, Switzerland.
⁴ Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada; Ottawa Institute of Systems Biology (OISB), Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada; Center for Neuromuscular Disease (CNMD), Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
⁵ Interdisciplinary School of Health Sciences, Faculty of Health Sciences, University of Ottawa, Ottawa, ON, Canada; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada. Electronic address: yburell2@uottawa.ca.

PMID: 38579709
DOI: 10.1016/j.stemcr.2024.03.004

Abstract

Maintenance of mitochondrial function plays a crucial role in the regulation of muscle stem cell (MuSC), but the underlying mechanisms remain ill defined. In this study, we monitored mitophagy in MuSCS under various myogenic states and examined the role of PINK1 in maintaining regenerative capacity. Results indicate that quiescent MuSCs actively express mitophagy genes and exhibit a measurable mitophagy flux and prominent mitochondrial localization to autophagolysosomes, which become rapidly decreased during activation. Genetic disruption of Pink1 in mice reduces PARKIN recruitment to mitochondria and mitophagy in quiescent MuSCs, which is accompanied by premature activation/commitment at the expense of self-renewal and progressive loss of muscle regeneration, but unhindered proliferation and differentiation capacity. Results also show that impaired fate decisions in PINK1-deficient MuSCs can be restored by scavenging excess mitochondrial ROS. These data shed light on the regulation of mitophagy in MuSCs and position PINK1 as an important regulator of their mitochondrial properties and fate decisions.

Keywords: fate decision; mitochondria; mitochondrial quality control; mitophagy; muscle regeneration; muscle stem cells.