Mitophagy-driven mitochondrial rejuvenation regulates stem cell fate.
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 fromPINK1 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.
Cancer Research Group, Latvian Biomedical Research and Study Centre, Riga, Latvia.
Alejandro
A
Vazquez-Martin
Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, Katholieke Universiteit Leuven, Leuven, Flanders, Belgium.
Chris
C
Van den Haute
Josep Carreras Leukemia Research Institute, Stem Cell Lab, Barcelona, Spain.
Sílvia
S
Cufí
Molecular Oncology Group, Girona Biomedical Research Institute (IDIBGI), Girona, Spain.
Bruna
B
Corominas-Faja
Molecular Oncology Group, Girona Biomedical Research Institute (IDIBGI), Girona, Spain.
Elisabet
E
Cuyàs
Department of Anatomical Pathology, Dr. Josep Trueta Hospital of Girona, Girona, Catalonia, Spain.
Eugeni
E
Lopez-Bonet
Unitat de Recerca Biomèdica, Hospital Universitari Sant Joan, Institut d'Investigació Sanitaria Pere Virgili (IISPV), Universitat Rovira i Virgili, Reus, Spain.
Esther
E
Rodriguez-Gallego
Unitat de Recerca Biomèdica, Hospital Universitari Sant Joan, Institut d'Investigació Sanitaria Pere Virgili (IISPV), Universitat Rovira i Virgili, Reus, Spain.
Salvador
S
Fernández-Arroyo
Unitat de Recerca Biomèdica, Hospital Universitari Sant Joan, Institut d'Investigació Sanitaria Pere Virgili (IISPV), Universitat Rovira i Virgili, Reus, Spain.
Jorge
J
Joven
Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, Katholieke Universiteit Leuven, Leuven, Flanders, Belgium.
Veerle
V
Baekelandt
Molecular Oncology Group, Girona Biomedical Research Institute (IDIBGI), Girona, Spain.|ProCURE (Program Against Cancer Therapeutic Resistance), Metabolism and Cancer Group, Catalan Institute of Oncology, Girona, Spain.
Javier A
JA
Menendez
D000818:Animals; D019070:Cell Lineage / Q000502:physiology*; D065150:Cellular Reprogramming / Q000502:physiology; D004734:Energy Metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D055432:Metabolomics; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D063306:Mitophagy / Q000502:physiology*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D000099202:PTEN-Induced Putative Kinase
D011494:Protein Kinases; D000099202:PTEN-Induced Putative Kinase
cancer; epigenetics; mitochondria; mitophagy; pluripotency; stem cells