A muscle-enriched mitochondrial protein regulates postnatal heart growth through mitonuclear ubiquinone–PPAR signaling

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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Journal
Proceedings of the National Academy of Sciences
Published
2026-10-16
DOI
https://doi.org/10.1073/pnas.2619615123
Primary Topic
Coenzyme Q10 studies and effects
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article
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article

A muscle-enriched mitochondrial protein regulates postnatal heart growth through mitonuclear ubiquinone–PPAR signaling

Matthew P. Jacobson, Sheamin Khyeam, Haruko Nakano, Emanuele Barca et al.
Proceedings of the National Academy of Sciences
Coenzyme Q10 studies and effects
article

A muscle-enriched mitochondrial protein regulates postnatal heart growth through mitonuclear ubiquinone–PPAR signaling

Matthew P. Jacobson, Sheamin Khyeam, Haruko Nakano, Emanuele Barca, Arun Padmanabhan, Guo N. Huang, Masatoshi Murai, Takeshi Yoneshiro, C. Chen, Catarina Maria Quinzii, Xiaoxin Chen, Chakrapani Kalyanaraman, Austin Hsu, Atsushi Nakano, Yoshitaka Fujihara, Mark T. Waddingham, Saptarsi M. Haldar, James T. Pearson, Makoto Nakamura, Kinya Otsu, Kentaro Hirose, Shingo Kajimura, Hao Zhang, Kazuki Tajima, Sara Gonzalez Ortega, Steven R. Chang, Jiajia Wang, Guang Hu, Feng Zhang, Hongyao Yu, Shun Yao
article en

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.

Proceedings of the National Academy of SciencesVol. 123(42)
Beth Israel Deaconess Medical Center (US), Gladstone Institutes (US), University of California, San Francisco (US), Wellcome/MRC Cambridge Stem Cell Institute (GB), Kyoto University (JP), University of Cambridge (GB), Columbia University Irving Medical Center (US), University of California System (US), National Institute of Environmental Health Sciences (US), National Cerebral and Cardiovascular Center (JP)
Good health and well-being
Openalex Percentile: Top 24%
Coenzyme Q10 studies and effects
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