Mpc2 is a subunit of the mitochondrial pyruvate carrier (MPC) complex. The MPC is crucial as it transports pyruvate, produced by glycolysis in the cytosol, across the inner mitochondrial membrane into the mitochondrial matrix. This process links cytosolic and mitochondrial metabolism, playing a vital role in fundamental metabolic pathways such as the tricarboxylic acid cycle, ATP generation, and biosynthesis of various molecules. It has been associated with numerous metabolic and physiological processes, making it a potential target for treating various diseases [2,3].

Genetic ablation of Mpc2 in adult murine hearts was sufficient to induce hypertrophy and heart failure, indicating its essential role in maintaining normal cardiac function [1]. In mice, genetic inactivation of Mpc2 led to basal cell hyperplasia and reduced ciliated cells during homeostasis in the airway, as well as delayed epithelial regeneration after injury, suggesting its importance in airway basal progenitor cell function [5]. In obese, hepatocyte-specific Mpc2 knockout (LS-Mpc2-/-) mice, there was reduced phosphorylation of the rate-limiting enzyme in branched-chain amino acid (BCAA) catabolism, accompanied by activation of mTOR signaling, revealing a cross-talk between mitochondrial pyruvate and BCAA metabolism [4].

In conclusion, Mpc2 is essential for normal physiological function, especially in processes related to mitochondrial pyruvate metabolism. Studies using Mpc2 knockout or conditional knockout mouse models have provided valuable insights into its role in heart failure, airway cell function, and BCAA metabolism, highlighting its potential significance in understanding and treating related diseases.

References:

1. Cluntun, Ahmad A, Badolia, Rachit, Lettlova, Sandra, Rutter, Jared, Drakos, Stavros G. 2020. The pyruvate-lactate axis modulates cardiac hypertrophy and heart failure. In Cell metabolism, 33, 629-648.e10. doi:10.1016/j.cmet.2020.12.003. https://pubmed.ncbi.nlm.nih.gov/33333007/

2. Tavoulari, Sotiria, Sichrovsky, Maximilian, Kunji, Edmund R S. 2023. Fifty years of the mitochondrial pyruvate carrier: New insights into its structure, function, and inhibition. In Acta physiologica (Oxford, England), 238, e14016. doi:10.1111/apha.14016. https://pubmed.ncbi.nlm.nih.gov/37366179/

3. Yiew, Nicole K H, Finck, Brian N. 2022. The mitochondrial pyruvate carrier at the crossroads of intermediary metabolism. In American journal of physiology. Endocrinology and metabolism, 323, E33-E52. doi:10.1152/ajpendo.00074.2022. https://pubmed.ncbi.nlm.nih.gov/35635330/

4. Ferguson, Daniel, Eichler, Sophie J, Yiew, Nicole K H, Niemi, Natalie M, Finck, Brian N. 2023. Mitochondrial pyruvate carrier inhibition initiates metabolic crosstalk to stimulate branched chain amino acid catabolism. In Molecular metabolism, 70, 101694. doi:10.1016/j.molmet.2023.101694. https://pubmed.ncbi.nlm.nih.gov/36801448/

5. Li, Yawen, He, Yalin, Zheng, Qi, Ren, Tao, Sui, Pengfei. 2024. Mitochondrial pyruvate carriers control airway basal progenitor cell function through glycolytic-epigenetic reprogramming. In Cell stem cell, 32, 105-120.e6. doi:10.1016/j.stem.2024.09.015. https://pubmed.ncbi.nlm.nih.gov/39426380/