Charles Peter Ng, MD/PhD — Physician-Scientist, Memorial Sloan Kettering

Background

Schematic of a mitochondrion and a nucleus. Mitochondrial activity produces ATP and the metabolites alpha-ketoglutarate, acetyl-CoA and succinate. An arrow runs from the mitochondrion to chromatin in the nucleus, with a question mark over gene expression. — How do mitochondria communicate with chromatin? Metabolites such as α-ketoglutarate, acetyl-CoA and succinate are established signals. I ask whether mitochondrial ATP also has a role.

Metabolism responds to environmental cues and shapes cellular behavior. I study how metabolism regulates gene expression, with a focus on mechanisms that deliver ATP to the nucleus and buffer its availability within it.

I did my MD/PhD at NYU, where my thesis work with Dan Littman established how the Cd4 locus is heritably silenced in cytotoxic T cells, using CD4 silencing as a lineage marker for epigenetic memory. I then trained as a physician-scientist at Weill Cornell, in anatomic pathology and the Physician-Scientist Training Program, where I remain a trainee. I currently work in Craig Thompson’s laboratory at Memorial Sloan Kettering at the interface of metabolism, chromatin, and antitumor immunity, supported by a Tow Foundation Postdoctoral Fellowship.

Research

In my postdoctoral work (Ng et al., Cell, 2026), I showed that D-alpha-hydroxybutyrate — a short-chain alpha-hydroxy acid of microbial origin — acts as a signaling molecule that switches CD8⁺ T cells from glycolysis to fatty-acid-supported oxidative phosphorylation, builds a phosphocreatine reserve, and drives ATP-dependent chromatin remodeling at effector loci, enhancing antitumor function in both mouse and human T cells.

I follow ATP delivery rather than the provision of substrates such as acetyl-CoA for acetylation or SAM for methylation. Blocking ATP synthase leaves DAHB-induced histone acetylation intact but abolishes effector gene induction.

Three questions organize the laboratory I am building. I ask how ATP delivery to chromatin is regulated in space and time, how D-2-hydroxyacids set bioenergetics both within a cell and across the whole animal, and how metabolic stress signaling selects which effector genes a T cell expresses. Together they point toward new therapeutic strategies for antitumor immunity and metabolic disease.

Schematic of a CD8+ T cell. D-alpha-hydroxybutyrate stimulates the mitochondrial electron transport chain, raising oxidative phosphorylation and fatty acid oxidation. Mitochondrial creatine kinase charges phosphocreatine, which passes into the nucleus where creatine kinase B transfers its phosphate to ADP to regenerate ATP. That ATP supports BAF-dependent chromatin remodeling and increased accessibility at effector loci, raising perforin, interferon gamma and TNF-alpha, driving cytotoxicity toward the tumor and away from exhaustion. — DAHB raises mitochondrial ATP production and expands the phosphocreatine reserve. Creatine kinase B regenerates ATP within the nucleus, supporting BAF-dependent chromatin remodeling at effector loci. From Ng et al., *Cell*, 2026.

Phosphagen systems as spatial ATP delivery

Chromatin remodeling consumes ATP, but ATP does not travel freely through a crowded nucleus. I am testing whether the creatine/phosphocreatine shuttle is what delivers it — mapping creatine kinase B and its partners at chromatin, reading nuclear ATP directly with targeted sensors, and then engineering orthogonal phosphagen circuits into T cells, a cell-engineering strategy that modifies energy supply rather than signaling.

Fluorescence micrographs of CD8+ T cell nuclei expressing a nuclear-targeted ATP sensor, in T cell media, with a creatine kinase inhibitor, and with 2-deoxyglucose plus oligomycin. The ATP sensor signal falls progressively across the three conditions while the HaloTag reference is unchanged. Beside them, a scatter plot of the ATP sensor to HaloTag ratio for the same three conditions. — A, CD8⁺ T cell nuclei expressing a nuclear-targeted ATP sensor (green) alongside a HaloTag reference (magenta), in T cell media, with a creatine kinase inhibitor (CKi), and with 2-deoxyglucose plus oligomycin. B, the ATP sensor to HaloTag ratio across the same three conditions. The sensor signal falls while the reference is unchanged, so the readout reports ATP in the nucleus and not how much sensor is present.

D-2-hydroxyacids as signaling molecules

D-alpha-hydroxybutyrate acts through its stereochemistry rather than through its metabolism. The mirror-image L form does not substitute, and my data show the sensor is not LDHD, the enzyme that consumes it. I am identifying the protein that reads the D configuration — and following the same chemistry outside the immune system, where oral DAHB limits diet-induced weight gain through a mechanism that requires LDHD in the intestinal epithelium.

Three mice photographed side by side against a ruler: normal diet with saline, high-fat diet with saline, and high-fat diet with DAHB. The high-fat saline animal is markedly larger. Beside them, a schematic of DAHB crossing into an intestinal epithelial cell and being oxidised by LDHD to alpha-ketobutyrate. — A, oral DAHB limits weight gain on a high-fat diet. B, DAHB is oxidised by LDHD in the intestinal epithelium, producing α-ketobutyrate (AKB) and reducing FAD to FADH₂.

Integration of energetic stress

Energetic stress engages several sensors at once — the integrated stress response, AMPK, mTORC1, the heat-shock arm — and my published data show the ISR alone does not account for which effector genes open. I am mapping which stress kinases are engaged using high-resolution single-cell techniques.

Three-panel figure. A, scatter of metabolic genes comparing what cyclocreatine and oligomycin do to them; ATF4 target genes of the integrated stress response rise only under oligomycin. B, the same comparison for effector genes; both drugs suppress the programme, and only Lta, Il17a and Tnf rise under oligomycin. C, schematic of a cell under metabolic stress, with AMPK, the ISR, mTORC1 and the heat shock response above ATP and an arrow into the nucleus to effector genes. — A, oligomycin induces the integrated stress response, shown in green. B, both drugs suppress the effector programme, but oligomycin induces three effector genes — Lta, Il17a and Tnf. C, AMPK reads the AMP/ADP to ATP ratio, mTORC1 reads amino acid sufficiency, the ISR responds to amino acid limitation and to mitochondrial, ER and viral stress, and the heat-shock response senses cytosolic protein misfolding through HSF1. The hypothesis is that ATP availability couples these pathways and determines transcriptional outputs.

Selected publications

Mitochondrial ATP promotes T cell differentiation through chromatin accessibility Ng C, Fung TS, Li D, Kropp KN, Somarribas Patterson LF, Markovitz A, Weinberg DN, Jones O, Kim JY, Zhang G, … Thompson CB Cell 2026. 10.1016/j.cell.2026.08.023 · PMID 42727574
Lactate activates the mitochondrial electron transport chain independently of its metabolism Cai X, Ng CP, Jones O, Fung TS, Ryu KW, Li D, Thompson CB Molecular Cell 2023;83:3904–3920.e7. 10.1016/j.molcel.2023.09.034
The histone chaperone CAF-1 cooperates with the DNA methyltransferases to maintain Cd4 silencing in cytotoxic T cells Ng C, Aichinger M, Nguyen T, Au C, Najar T, Wu L, Mesa KR, Liao W, Quivy JP, Hubert B, Almouzni G, Zuber J, Littman DR Genes & Development 2019;33:669–683. 10.1101/gad.322024.118

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