A Micropeptide Component of the OGDH Complex Modulates ATP Production in the TCA Cycle.
6 affiliations
- 1School of Basic Medicine and Forensic Medicine, North Sichuan Medical College, Nanchong, People's Republic of China.
- 2The Engineering Research Center of Synthetic Polypeptide Drug Discovery and Evaluation, China Pharmaceutical University, Nanjing, Jiangsu, People's Republic of China.
- 3Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China.
- 4Mudi Meng Honors College, China Pharmaceutical University, Nanjing, People's Republic of China.
- 5State Key Laboratory of Natural Medicines, Ministry of Education, China Pharmaceutical University, Nanjing, People's Republic of China.
- 6Joint International Research Laboratory of Target Discovery and New Drug Innovation, MOE, Nanjing, People's Republic of China.
Abstract
Since its elucidation, the tricarboxylic acid (TCA) cycle has been regarded as a fully defined enzymatic pathway. Here, we report the discovery of a previously unrecognized micropeptide component of this central metabolic system. Through analyzing ribosome profiling data from the mouse sORFs.org database, we discovered APPM (ATP production-promoting micropeptide), a 29-amino acid peptide encoded by a non-canonical small open reading frame within the mouse Ctsb gene. APPM localizes to the mitochondrial matrix and inner membrane, where it directly binds to the E1 subunit (OGDH) of the α-ketoglutarate dehydrogenase complex (OGDHc). This interaction modulates OGDHc enzymatic activity, thereby regulating NADH and ATP production. We identified tyrosine-13 as the critical residue mediating the APPM-OGDH interaction and functional activation. Exogenous APPM administration increased ATP levels in vivo and, in a mouse model of heart failure, restored cardiac function, outperforming the reference drug trimetazidine. Collectively, our findings identify APPM as the first micropeptide regulator of the OGDH complex, expanding the known repertoire of the TCA cycle and presenting a potential therapeutic strategy for diseases characterized by bioenergetic insufficiency.
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BibTeX
@article{yin2026micropeptide,
title = {{A Micropeptide Component of the OGDH Complex Modulates ATP Production in the TCA Cycle.}},
author = {Xinqiang Yin and Weiyan Qi and Lifen Lin and Huilin Zheng and Guoxiang Zhao and Quan Chen and Guoqiang Shao and Yifan Wu and Jialiang Hu and Hanmei Xu},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
year = {2026},
month = oct,
doi = {10.1002/advs.77242},
url = {https://europepmc.org/article/MED/42893408},
note = {CC BY},
}
RIS
TY - JOUR
TI - A Micropeptide Component of the OGDH Complex Modulates ATP Production in the TCA Cycle.
AU - Xinqiang Yin
AU - Weiyan Qi
AU - Lifen Lin
AU - Huilin Zheng
AU - Guoxiang Zhao
AU - Quan Chen
AU - Guoqiang Shao
AU - Yifan Wu
AU - Jialiang Hu
AU - Hanmei Xu
PY - 2026
DA - 2026/10/18
JO - Advanced science (Weinheim, Baden-Wurttemberg, Germany)
DO - 10.1002/advs.77242
UR - https://europepmc.org/article/MED/42893408
AB - Since its elucidation, the tricarboxylic acid (TCA) cycle has been regarded as a fully defined enzymatic pathway. Here, we report the discovery of a previously unrecognized micropeptide component of this central metabolic system. Through analyzing ribosome profiling data from the mouse sORFs.org database, we discovered APPM (ATP production-promoting micropeptide), a 29-amino acid peptide encoded by a non-canonical small open reading frame within the mouse Ctsb gene. APPM localizes to the mitochondrial matrix and inner membrane, where it directly binds to the E1 subunit (OGDH) of the α-ketoglutarate dehydrogenase complex (OGDHc). This interaction modulates OGDHc enzymatic activity, thereby regulating NADH and ATP production. We identified tyrosine-13 as the critical residue mediating the APPM-OGDH interaction and functional activation. Exogenous APPM administration increased ATP levels in vivo and, in a mouse model of heart failure, restored cardiac function, outperforming the reference drug trimetazidine. Collectively, our findings identify APPM as the first micropeptide regulator of the OGDH complex, expanding the known repertoire of the TCA cycle and presenting a potential therapeutic strategy for diseases characterized by bioenergetic insufficiency.
SN - 2198-3844
ER -