# Fine-tuning of mitochondrial Complex I activity in CD8 cells

> **NIH NIH R21** · UNIVERSITY OF COLORADO DENVER · 2020 · $247,260

## Abstract

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.

## Key facts

- **NIH application ID:** 9876384
- **Project number:** 1R21AI149187-01
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Mercedes Rincon
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $247,260
- **Award type:** 1
- **Project period:** 2020-01-31 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9876384

## Citation

> US National Institutes of Health, RePORTER application 9876384, Fine-tuning of mitochondrial Complex I activity in CD8 cells (1R21AI149187-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9876384. Licensed CC0.

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