Increased mitochondrial mutation heteroplasmy induces aging phenotypes in pluripotent stem cells and their differentiated progeny

Amy R Vandiver; Alejandro Torres Jr; Amberly Sanden; Thang L Nguyen; Jasmine Gasilla; Mary T Doan; Vahan Martirosian; Austin Hoang; Jonathan Wanagat; Michael A Teitell

doi:10.1111/acel.14402

Increased mitochondrial mutation heteroplasmy induces aging phenotypes in pluripotent stem cells and their differentiated progeny

Aging Cell. 2024 Dec 16:e14402. doi: 10.1111/acel.14402. Online ahead of print.

Authors

Amy R Vandiver^{1

2}, Alejandro Torres Jr³, Amberly Sanden^{3

4}, Thang L Nguyen³, Jasmine Gasilla¹, Mary T Doan⁵, Vahan Martirosian³, Austin Hoang⁶, Jonathan Wanagat^{2

6}, Michael A Teitell^{3

7

8

9

10}

Affiliations

¹ Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA.
² Veterans Administration Greater Los Angeles Healthcare System, Los Angeles, California, USA.
³ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA.
⁴ Department of Biology, California State University Northridge, California, USA.
⁵ Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA.
⁶ Division of Geriatrics, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA.
⁷ Molecular Biology Institute, University of California at Los Angeles, Los Angeles, California, USA.
⁸ Department of Bioengineering, California Nano Systems Institute, and Broad Center for Regenerative Medicine and Stem Cell Research, University of California at Los Angeles, Los Angeles, California, USA.
⁹ Department of Pediatrics, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA.
¹⁰ Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA.

PMID: 39680477
DOI: 10.1111/acel.14402

Abstract

The mitochondrial genome (mtDNA) is an important source of inherited extranuclear variation. Clonal increases in mtDNA mutation heteroplasmy have been implicated in aging and disease, although the impact of this shift on cell function is challenging to assess. Reprogramming to pluripotency affects mtDNA mutation heteroplasmy. We reprogrammed three human fibroblast lines with known heteroplasmy for deleterious mtDNA point or deletion mutations. Quantification of mutation heteroplasmy in the resulting 76 induced pluripotent stem cell (iPSC) clones yielded a bimodal distribution, creating three sets of clones with high levels or absent mutation heteroplasmy with matched nuclear genomes. iPSC clones with elevated deletion mutation heteroplasmy show altered growth dynamics, which persist in iPSC-derived progenitor cells. We identify transcriptomic and metabolic shifts consistent with increased investment in neutral lipid synthesis as well as increased epigenetic age in high mtDNA deletion mutation iPSC, consistent with changes occurring in cellular aging. Together, these data demonstrate that high mtDNA mutation heteroplasmy induces changes occurring in cellular aging.

Keywords: aging; iPSC; mitochondria; mtDNA mutation.

© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Abstract

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