Proline restores mitochondrial function and reverses aging hallmarks in senescent cells
Debanik Choudhury,
Na Rong,
Hamsa Vardini Senthil Kumar,
Sydney Swedick,
Ronel Z. Samuel,
Pihu Mehrotra,
John Toftegaard,
Nika Rajabian,
Ramkumar Thiyagarajan,
Ashis K. Podder,
Yulun Wu,
Shahryar Shahini,
Kenneth L. Seldeen,
Bruce Troen,
Pedro Lei,
Stelios T. Andreadis
Affiliations
Debanik Choudhury
Department of Chemical and Biological Engineering, University at Buffalo, Buffalo, NY 14260, USA
Na Rong
Department of Chemical and Biological Engineering, University at Buffalo, Buffalo, NY 14260, USA
Hamsa Vardini Senthil Kumar
Department of Genetics, Genomics and Bioinformatics, University at Buffalo, Buffalo, NY 14263, USA
Sydney Swedick
Department of Biomedical Engineering, University at Buffalo, Buffalo, NY 14260, USA
Ronel Z. Samuel
Department of Chemical and Biological Engineering, University at Buffalo, Buffalo, NY 14260, USA
Pihu Mehrotra
Department of Chemical and Biological Engineering, University at Buffalo, Buffalo, NY 14260, USA
John Toftegaard
Department of Biomedical Engineering, University at Buffalo, Buffalo, NY 14260, USA
Nika Rajabian
Department of Chemical and Biological Engineering, University at Buffalo, Buffalo, NY 14260, USA
Ramkumar Thiyagarajan
Department of Medicine, Division of Geriatrics and Palliative Medicine, Buffalo, NY 14203, USA
Ashis K. Podder
Department of Chemical and Biological Engineering, University at Buffalo, Buffalo, NY 14260, USA
Yulun Wu
Department of Chemical and Biological Engineering, University at Buffalo, Buffalo, NY 14260, USA
Shahryar Shahini
Department of Chemical and Biological Engineering, University at Buffalo, Buffalo, NY 14260, USA
Kenneth L. Seldeen
Department of Medicine, Division of Geriatrics and Palliative Medicine, Buffalo, NY 14203, USA
Bruce Troen
Department of Medicine, Division of Geriatrics and Palliative Medicine, Buffalo, NY 14203, USA
Pedro Lei
Department of Chemical and Biological Engineering, University at Buffalo, Buffalo, NY 14260, USA
Stelios T. Andreadis
Department of Chemical and Biological Engineering, University at Buffalo, Buffalo, NY 14260, USA; Department of Biomedical Engineering, University at Buffalo, Buffalo, NY 14260, USA; Center of Excellence in Bioinformatics and Life Sciences, University at Buffalo, Buffalo, NY 14263, USA; Center for Cell, Gene and Tissue Engineering (CGTE), University at Buffalo, Buffalo, NY 14260, USA; Corresponding author
Summary: Mitochondrial dysfunction is a hallmark of cellular senescence, with the loss of mitochondrial function identified as a potential causal factor contributing to senescence-associated decline in cellular functions. Our recent findings revealed that ectopic expression of the pluripotency transcription factor NANOG rejuvenates dysfunctional mitochondria of senescent cells by rewiring metabolic pathways. In this study, we report that NANOG restores the expression of key enzymes, PYCR1 and PYCR2, in the proline biosynthesis pathway. Additionally, senescent mesenchymal stem cells manifest severe mitochondrial respiratory impairment, which is alleviated through proline supplementation. Proline induces mitophagy by activating AMP-activated protein kinase α and upregulating Parkin expression, enhancing mitochondrial clearance and ultimately restoring cell metabolism. Notably, proline treatment also mitigates several aging hallmarks, including DNA damage, senescence-associated β-galactosidase, inflammatory cytokine expressions, and impaired myogenic differentiation capacity. Overall, this study highlights the role of proline in mitophagy and its potential in reversing senescence-associated mitochondrial dysfunction and aging hallmarks.
