MCJ/DnaJC15, an Endogenous Mitochondrial Repressor of the Respiratory Chain That Controls Metabolic Alterations

Abstract

Mitochondria are the main engine that generates ATP through oxidative phosphorylation within the respiratory chain. Mitochondrial respiration is regulated according to the metabolic needs of cells and can be modulated in response to metabolic changes. Little is known about the mechanisms that regulate this process. Here, we identify MCJ/DnaJC15 as a distinct cochaperone that localizes at the mitochondrial inner membrane, where it interacts preferentially with complex I of the electron transfer chain. We show that MCJ impairs the formation of supercomplexes and functions as a negative regulator of the respiratory chain. The loss of MCJ leads to increased complex I activity, mitochondrial membrane potential, and ATP production. Although MCJ is dispensable for mitochondrial function under normal physiological conditions, MCJ deficiency affects the pathophysiology resulting from metabolic alterations. Thus, enhanced mitochondrial respiration in the absence of MCJ prevents the pathological accumulation of lipids in the liver in response to both fasting and a high-cholesterol diet. Impaired expression or loss of MCJ expression may therefore result in a “rapid” metabolism that mitigates the consequences of metabolic disorders.

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ACKNOWLEDGMENTS

We thank Marilyn Wadsworth and Nicole Bishop (Microscopy Imaging Center, University of Vermont, Burlington, VT) for help with confocal microscopy and immunoelectron microscopy, Timothy Hunter and Mary Lou Shane (DNA Sequencing Facility, University of Vermont, Burlington, VT) for assistance with real-time RT-PCR analysis, Colette Charland (Flow Cytometry Facility, University of Vermont, Burlington, VT) for help with flow cytometry analysis, Itziar Martín (CIC bioGUNE, Derio, Bizkaia, Spain) for technical assistance, and Sebastian Hasenfuss (CNIO, Madrid, Spain) and Guadalupe Sabio (CNIO) for helpful discussions.

This work was supported by NIH grants CA127099 (M. Rincon), Lake Champlain Cancer Research Organization (M. Rincon), Fundacion Jesus Serra (M. Rincon), AI078277 (J. Anguita), and GM068650 (M. Radermacher).