TY - JOUR
T1 - Reversible compromise of physiological resilience by accumulation of heteroplasmic mtDNA mutations
AU - Huang, Huihui
AU - Wang, Yi
AU - Zsengeller, Zsuzsanna K.
AU - Gorham, Joshua M.
AU - Vemireddy, Vamsidhara
AU - Clark, Amanda J.
AU - Pan, Hui
AU - Dreyfuss, Jonathan M.
AU - Jotwani, Vasantha
AU - Shlipak, Michael G.
AU - Sarnak, Mark J.
AU - Parikh, Chirag R.
AU - Thiessen-Philbrook, Heather
AU - Katz, Ronit
AU - Waikar, Sushrut S.
AU - Lake, Nicole J.
AU - Lek, Monkol
AU - Shi, Wen
AU - Puiu, Daniela
AU - Hong, Yun Soo
AU - Seidman, Jonathan G.
AU - Arking, Dan E.
AU - Parikh, Samir M.
N1 - Publisher Copyright:
Copyright © 2025 the authors, some rights reserved;
PY - 2025/10/9
Y1 - 2025/10/9
N2 - Somatically acquired mitochondrial DNA (mtDNA) mutations accumulate with age, but the mechanisms and consequences of this accumulation are poorly understood. Here we show that transient injuries induce a burst of persistent mtDNA mutations that impair resilience to future injuries. mtDNA mutations suppressed energy-intensive nucleotide metabolism. repletion of adenosine, but not other nucleotides, restored adenosine triphosphate generation, which required a nuclear-encoded purine biosynthetic enzyme, adenylate kinase 4 (AK4). Analysis of 369,912 UK biobank participants revealed a graded association between mutation burden and chronic kidney disease severity as well as an independent increase in the risk of future acute kidney injury events (P < 10−7). Heteroplasmic mtDNA mutations may therefore reflect the cumulative effect of acute injuries to metabolically active cells, impairing major functions in a fashion amenable to nuclear-controlled purine biosynthesis.
AB - Somatically acquired mitochondrial DNA (mtDNA) mutations accumulate with age, but the mechanisms and consequences of this accumulation are poorly understood. Here we show that transient injuries induce a burst of persistent mtDNA mutations that impair resilience to future injuries. mtDNA mutations suppressed energy-intensive nucleotide metabolism. repletion of adenosine, but not other nucleotides, restored adenosine triphosphate generation, which required a nuclear-encoded purine biosynthetic enzyme, adenylate kinase 4 (AK4). Analysis of 369,912 UK biobank participants revealed a graded association between mutation burden and chronic kidney disease severity as well as an independent increase in the risk of future acute kidney injury events (P < 10−7). Heteroplasmic mtDNA mutations may therefore reflect the cumulative effect of acute injuries to metabolically active cells, impairing major functions in a fashion amenable to nuclear-controlled purine biosynthesis.
UR - https://www.scopus.com/pages/publications/105018318026
UR - https://www.scopus.com/pages/publications/105018318026#tab=citedBy
U2 - 10.1126/science.adk7978
DO - 10.1126/science.adk7978
M3 - Article
C2 - 40906782
AN - SCOPUS:105018318026
SN - 0036-8075
VL - 390
SP - 164
EP - 172
JO - Science
JF - Science
IS - 6769
ER -