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Research Paper|Volume 8, Issue 7|pp 1330—1349

Mitophagy-driven mitochondrial rejuvenation regulates stem cell fate

Alejandro Vazquez-Martin1, Chris Van Van den Haute2, Sílvia Cufí3, Bruna Corominas Corominas-Faja4, Elisabet Cuyàs4, Eugeni Lopez-Bonet5, Esther Rodriguez-Gallego6, Salvador Fernández-Arroyo6, Jorge Joven6, Veerle Baekelandt2, Javier A. A. Menendez4,7
  • 1Cancer Research Group, Latvian Biomedical Research & Study Centre, Riga, Latvia
  • 2Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, Katholieke Universiteit Leuven, Leuven, Flanders, Belgium
  • 3Josep Carreras Leukemia Research Institute, Stem Cell Lab, Barcelona, Spain
  • 4Molecular Oncology Group, Girona Biomedical Research Institute (IDIBGI), Girona, Spain
  • 5Department of Anatomical Pathology, Dr. Josep Trueta Hospital of Girona, Girona, Catalonia, Spain
  • 6Unitat de Recerca Biomèdica, Hospital Universitari Sant Joan, Institut d'Investigació Sanitaria Pere Virgili (IISPV), Universitat Rovira i Virgili, Reus, Spain
  • 7ProCURE (Program Against Cancer Therapeutic Resistance), Metabolism and Cancer Group, Catalan Institute of Oncology, Girona, Spain
Received: February 11, 2016Accepted: May 30, 2016Published: June 13, 2016
https://doi.org/10.18632/aging.100976

Copyright: © 2016 Vazquez-Martin et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Our understanding on how selective mitochondrial autophagy, or mitophagy, can sustain the archetypal properties of stem cells is incomplete. PTEN-induced putative kinase 1 (PINK1) plays a key role in the maintenance of mitochondrial morphology and function and in the selective degradation of damaged mitochondria by mitophagy. Here, using embryonic fibroblasts from PINK1 gene-knockout (KO) mice, we evaluated whether mitophagy is a causal mechanism for the control of cell-fate plasticity and maintenance of pluripotency. Loss of PINK1-dependent mitophagy was sufficient to dramatically decrease the speed and efficiency of induced pluripotent stem cell (iPSC) reprogramming. Mitophagy-deficient iPSC colonies, which were characterized by a mixture of mature and immature mitochondria, seemed unstable, with a strong tendency to spontaneously differentiate and form heterogeneous populations of cells. Although mitophagy-deficient iPSC colonies normally expressed pluripotent markers, functional monitoring of cellular bioenergetics revealed an attenuated glycolysis in mitophagy-deficient iPSC cells. Targeted metabolomics showed a notable alteration in numerous glycolysis- and TCA-related metabolites in mitophagy-deficient iPSC cells, including a significant decrease in the intracellular levels of α-ketoglutarate -a key suppressor of the differentiation path in stem cells. Mitophagy-deficient iPSC colonies exhibited a notably reduced teratoma-initiating capacity, but fully retained their pluripotency and multi-germ layer differentiation capacity in vivo. PINK1-dependent mitophagy pathway is an important mitochondrial switch that determines the efficiency and quality of somatic reprogramming. Mitophagy-driven mitochondrial rejuvenation might contribute to the ability of iPSCs to suppress differentiation by directing bioenergetic transition and metabolome remodeling traits. These findings provide new insights into how mitophagy might influence the stem cell decisions to retain pluripotency or differentiate in tissue regeneration and aging, tumor growth, and regenerative medicine.