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

Abstract

e 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.

Functional Diversity of Human Mitochondrial J-proteins Is Independent of Their Association with the Inner Membrane Presequence Translocase

“…J and K, yeast cells were incubated untreated (J) or treated with 300 M cisplatin (K), and the growth of cells were monitored at 30°C. mas, thus suggesting a possible role of JC15⅐Magmas subcomplex in regulation of respiratory activity (22,34). Moreover, a specific loss of expression of JC15, especially in tissues of epithelial origin, results in development of chemoresistance against various chemotherapeutic drugs (30).…”

“…Hence, it was suggested that loss of expression of JC15 contributes to the malignant phenotype by conferring resistance to various anti-cancer drugs by modulating the chemotherapeutic response of the cancer cells and served as a molecular marker for the response to chemotherapy (29,31). Evidence also suggests JC15 to be a modulator of respiratory chain activity where it acts as an inhibitor of complex I (34). In contrast, a loss of function mutation in the J-domain of JC19 leads to a severe pathophysiological disorder, dilated cardiomyopathy and ataxia (DCM) 3 syndrome, that is characterized by cardiomyopathy and ataxia (24).…”

Rewired Metabolism in Drug-resistant Leukemia Cells

“…Ovarian and breast cancer patients exposed to continuous chemotherapy exhibited lower levels of DNAJC15 protein and enhanced drug resistance (36,37). In addition, loss of DNAJC15 has been associated with P-gp overexpression and can modulate cellular responses to altered metabolic conditions by enhancing mitochondrial respiration (38,39). Transcripts encoding the DENN/MADD domain containing 2D protein (DENND2D) were also detected in CEM but not CEM/R2 cells.…”

Human mitochondrial COX1 assembly into cytochrome c oxidase at a glance

“…Moreover, apart from its function in protein transport, another function of DNAJC19 that is not related to protein transport is further supported by the observation that only the second putative yeast Pam18 ortholog, MCJ, rescues pam18D cells (Schusdziarra et al, 2013). Strikingly, it has also been suggested that MCJ regulates the activity of complex I and promotes incorporation of complex I into respiratory chain supercomplexes (Hatle et al, 2013). These observations suggest that MCJ is present in two independent pools, because an association of the TIM23 complex with respiratory chain supercomplexes has not been described in humans.…”