Fine-tuning of mitochondrial Complex I activity in CD8 cells

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SUMMARY Metabolism is a key factor for CD8 T cell immune response. Mitochondria metabolism is essential for effector function of CD8 cells. Thus, strategies to enhance mitochondrial respiration could be used to improve efficacy of CD8 cell immune response. However, while there are a number of pharmacological reagents inhibiting different steps of the electron transport chain and/or synthesis mitochondrial ATP, enhancing mitochondrial activity is not easy. We have recently identified MCJ (Methylation-Controlled J protein, also called DnaJC15) as an endogenous negative regulator of Complex I and mitochondrial respiration. We have shown that loss of MCJ results in increased Complex I activity, MMP, mitochondrial respiration and ATP levels in CD8 cells. Increased mitochondrial respiration caused by loss of MCJ enhances cytokine secretion as well as cytotoxic activity. Thus, finding how MCJ interacts with Complex I and how it is regulated could lead to new strategies to disrupt this metabolic brake. The N-terminal region of MCJ (N-MCJ) has no homology to known eukaryotic proteins, but it retains specific sequence present only in bacterial proteins from different Alphaproteobacteria species. Interestingly, those bacterial proteins have an oxidoreductase activity, similarly to Complex I NADH dehydrogenase. N-MCJ interacts with NDUFv1, the subunit of Complex I that contains the NADH dehydrogenase activity to oxidize NADH to NAD+. Our recent computational analysis together with mass spectrometry suggest that N-MCJ can bind NAD+. We propose a model where MCJ acts as a dynamic negative regulator of Complex I with NAD+ as a sensor. When NAD+ levels produced by an active Complex I are elevated, NAD+ binds N-MCJ. Binding of NAD+ to N-MCJ then causes a structural change that makes N-MCJ accessible to interact with NDUFv1, and provide a negative feedback to Complex I to attenuate its activity and avoid overconsumption of limited metabolic substrates. We will investigate: 1) The binding of NAD+ to N-MCJ and its effect on N-MCJ conformational changes; 2) The dynamic interaction of N-MCJ with NDUFv1, its fine-tuning by NAD+ and the impact in mitochondrial respiration. Results from these studies could lead to the development of novel strategies and mechanisms to safely increase mitochondrial respiration in CD8 cells and enhance immune responses.