A muscle-enriched mitochondrial protein regulates postnatal heart growth through mitonuclear ubiquinone–PPAR signaling
Year: 2026
Type: article
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.
Authors: Kentaro Hirose, Xiaoxin Chen, Chakrapani Kalyanaraman, Mark T. Waddingham, Makoto Nakamura, Feng Zhang, Christina Chen, Shun Yao, Steven Chang, Hongyao Yu, Jiajia Wang, Emanuele Barca, Haruko Nakano, Austin Hsu, Sheamin Khyeam, Sara Gonzalez Ortega, Kazuki Tajima, Takeshi Yoneshiro, Hao Zhang, Arun Padmanabhan, Shingo Kajimura, Saptarsi Haldar, Atsushi Nakano, Masatoshi Murai, Yoshitaka Fujihara, Kinya Otsu, Catarina M. Quinzii, Matthew P. Jacobson, Guang Hu, James T. Pearson, Guo N. Huang
Institutions: Wellcome/MRC Cambridge Stem Cell Institute, University of Cambridge, University of California System, National Cerebral and Cardiovascular Center, National Institute of Environmental Health Sciences, Columbia University Irving Medical Center, Gladstone Institutes, University of California, San Francisco, Beth Israel Deaconess Medical Center, Kyoto University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
OpenAlex ID: W7222548702