A muscle-enriched mitochondrial protein regulates postnatal heart growth through mitonuclear ubiquinone-PPAR signaling.
18 affiliations
- 1Cardiovascular Research Institute, University of California, San Francisco, CA 94158.
- 2Department of Physiology, University of California, San Francisco, CA 94158.
- 3Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA 94158.
- 4Bakar Aging Research Institute, University of California, San Francisco, CA 94158.
- 5Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita 564-8565, Osaka, Japan.
- 6Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0AW, United Kingdom.
- 7Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158.
- 8Nine Square Therapeutics, Inc., South San Francisco, CA 94080.
- 9Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709.
- 10Department of Neurology, Columbia University Medical Center, New York, NY 10032.
- 11Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, CA 90095.
- 12Gladstone Institutes, San Francisco, CA 94158.
- 13University of California, San Francisco Diabetes Center, San Francisco, CA 94143.
- 14Department of Medicine, Division of Cardiology, University of California, San Francisco, CA 94158.
- 15Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215.
- 16Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan.
- 17Department of Advanced Medical Technologies, National Cerebral and Cardiovascular Center, Suita, Osaka 564-8565, Japan.
- 18Office of the President, National Cerebral and Cardiovascular Center, Suita, Osaka 564-8565, Japan.
Abstract
Increased mitochondrial biogenesis and aerobic respiration in postnatal mammalian organs are essential for adaptation to extrauterine life, yet the functions of many tissue-enriched, developmentally regulated mitochondrial proteins remain poorly defined. By integrating mitochondrial proteome annotations with mouse and human transcriptomic datasets, we identified Coenzyme Q10a (Coq10a), a striated muscle-enriched mitochondrial protein, as a regulator of postnatal cardiac growth. Coq10a, the mammalian homolog of the yeast ubiquinone-binding protein Coq10p, is highly induced in the heart after birth through thyroid hormone-, Nkx2.5-, and Tbx5-dependent regulation. To define its physiological function, we generated three independent Coq10a-deficient mouse models. Both global and cardiomyocyte-specific loss of Coq10a promoted postnatal cardiac hypertrophy without impairing basal cardiac function or mitochondrial respiration. Instead, Coq10a deficiency altered intracellular ubiquinone partitioning, resulting in increased ubiquinone accumulation in a microsomal membrane fraction. Transcriptomic analyses revealed enrichment of PPAR-associated metabolic gene sets and induction of established PPAR-responsive genes in Coq10a-deficient hearts. Pharmacological inhibition of PPARα and PPARγ, but not PPARδ, attenuated the hypertrophic phenotype. Molecular dynamics simulations, docking analyses, and mutagenesis identified PPARα residues that contribute to differential responsiveness to ubiquinone. Although Coq10a-deficient hearts maintained near-normal function under basal conditions, they exhibited increased susceptibility to pressure-overload stress. Together, these findings establish Coq10a as a regulator of intracellular ubiquinone partitioning and support a model linking altered mitochondrial lipid distribution and PPAR-associated signaling to postnatal cardiac growth. More broadly, they demonstrate how tissue-enriched mitochondrial proteins can mediate organ-specific physiological functions beyond energy production.
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BibTeX
@article{hirose2026muscleenriched,
title = {{A muscle-enriched mitochondrial protein regulates postnatal heart growth through mitonuclear ubiquinone-PPAR signaling.}},
author = {Kentaro Hirose and Xiaoxin Chen and Chakrapani Kalyanaraman and Mark T Waddingham and Makoto Nakamura and Feng Zhang and Christina Chen and Shun Yao and Steven Chang and Hongyao Yu and Jiajia Wang and Emanuele Barca and Haruko Nakano and Austin Hsu and Sheamin Khyeam and Sara Gonzalez Ortega and Kazuki Tajima and Takeshi Yoneshiro and Hao Zhang and Arun Padmanabhan and Shingo Kajimura and Saptarsi Haldar and Atsushi Nakano and Masatoshi Murai and Yoshitaka Fujihara and Kinya Otsu and Catarina M Quinzii and Matthew P Jacobson and Guang Hu and James T Pearson and Guo N Huang},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2026},
month = oct,
doi = {10.1073/pnas.2619615123},
url = {https://europepmc.org/article/MED/42886694},
note = {CC BY},
}
RIS
TY - JOUR
TI - A muscle-enriched mitochondrial protein regulates postnatal heart growth through mitonuclear ubiquinone-PPAR signaling.
AU - Kentaro Hirose
AU - Xiaoxin Chen
AU - Chakrapani Kalyanaraman
AU - Mark T Waddingham
AU - Makoto Nakamura
AU - Feng Zhang
AU - Christina Chen
AU - Shun Yao
AU - Steven Chang
AU - Hongyao Yu
AU - Jiajia Wang
AU - Emanuele Barca
AU - Haruko Nakano
AU - Austin Hsu
AU - Sheamin Khyeam
AU - Sara Gonzalez Ortega
AU - Kazuki Tajima
AU - Takeshi Yoneshiro
AU - Hao Zhang
AU - Arun Padmanabhan
AU - Shingo Kajimura
AU - Saptarsi Haldar
AU - Atsushi Nakano
AU - Masatoshi Murai
AU - Yoshitaka Fujihara
AU - Kinya Otsu
AU - Catarina M Quinzii
AU - Matthew P Jacobson
AU - Guang Hu
AU - James T Pearson
AU - Guo N Huang
PY - 2026
DA - 2026/10/16
JO - Proceedings of the National Academy of Sciences of the United States of America
DO - 10.1073/pnas.2619615123
UR - https://europepmc.org/article/MED/42886694
AB - Increased mitochondrial biogenesis and aerobic respiration in postnatal mammalian organs are essential for adaptation to extrauterine life, yet the functions of many tissue-enriched, developmentally regulated mitochondrial proteins remain poorly defined. By integrating mitochondrial proteome annotations with mouse and human transcriptomic datasets, we identified Coenzyme Q10a (Coq10a), a striated muscle-enriched mitochondrial protein, as a regulator of postnatal cardiac growth. Coq10a, the mammalian homolog of the yeast ubiquinone-binding protein Coq10p, is highly induced in the heart after birth through thyroid hormone-, Nkx2.5-, and Tbx5-dependent regulation. To define its physiological function, we generated three independent Coq10a-deficient mouse models. Both global and cardiomyocyte-specific loss of Coq10a promoted postnatal cardiac hypertrophy without impairing basal cardiac function or mitochondrial respiration. Instead, Coq10a deficiency altered intracellular ubiquinone partitioning, resulting in increased ubiquinone accumulation in a microsomal membrane fraction. Transcriptomic analyses revealed enrichment of PPAR-associated metabolic gene sets and induction of established PPAR-responsive genes in Coq10a-deficient hearts. Pharmacological inhibition of PPARα and PPARγ, but not PPARδ, attenuated the hypertrophic phenotype. Molecular dynamics simulations, docking analyses, and mutagenesis identified PPARα residues that contribute to differential responsiveness to ubiquinone. Although Coq10a-deficient hearts maintained near-normal function under basal conditions, they exhibited increased susceptibility to pressure-overload stress. Together, these findings establish Coq10a as a regulator of intracellular ubiquinone partitioning and support a model linking altered mitochondrial lipid distribution and PPAR-associated signaling to postnatal cardiac growth. More broadly, they demonstrate how tissue-enriched mitochondrial proteins can mediate organ-specific physiological functions beyond energy production.
SN - 0027-8424
SN - 1091-6490
ER -