The logic of the field has shifted because metabolites themselves turn out to be messengers. S-adenosylmethionine, or SAM, a product of one-carbon metabolism, serves as the methyl donor for chemical marks placed on mitochondrial DNA, including 5-methylcytosine and the bacteria-like N6-methyladenine. The methyltransferase METTL4 installs 6-methyladenine on mitochondrial DNA, which disrupts binding of the transcription factor TFAM and suppresses mitochondrial transcription. Hypoxia strongly induces METTL4 in liver and breast cancer cells, throttling mitochondrial metabolism precisely when tumors want it restrained. Methylation of the mitochondrial genome appears to protect it from oxidative damage, and DNA methyltransferases DNMT3A and DNMT3B mediate this in embryonic cells — enzymes whose aberrant expression or mutation drives cancer initiation. The picture is complicated, however: the true abundance of 5-methylcytosine on mitochondrial DNA remains debated, with optimized protocols reporting levels of only 0.19 to 0.67 percent in mouse oocytes and human lung carcinoma cells, and technical artifacts such as inefficient bisulfite conversion and mis-mapping of nuclear-integrated mitochondrial sequences continuing to muddy clinical analyses.

The replication machinery itself is equally metabolically entangled. DNA polymerase gamma, POLG, together with its accessory subunit POLG2, copies the mitochondrial genome, and its overactivation has been linked to elevated risk of prostate cancer and acute myeloid leukemia. Proteomic surveys have revealed a dense landscape of post-translational modifications on POLG and POLG2 that couple cellular fuel state to genome maintenance. The acetyltransferase GCN5 acetylates POLG at lysine 1039 using acetyl-CoA as donor, while the NAD+-dependent deacetylase SIRT3 reverses the mark — a push-pull system that reads acetyl-CoA and NAD+ availability directly. In parallel, poly(ADP-ribose) polymerase 1 uses NAD+ to attach ADP-ribose groups to POLG, triggering ubiquitination and degradation. Through these routes, the cell’s energy currency and redox state literally decide how much replication enzyme survives, and cancer cells exploit these metabolite-sensing nodes to rewire mitochondrial function to their advantage.

Transcription is governed by the same logic. The mitochondrial RNA polymerase POLRMT is succinylated at lysine 622, a modification that impairs its DNA-binding activity. The metabolic enzyme SUCLG1, part of the succinyl-CoA ligase complex, restricts mitochondrial succinyl-CoA levels to keep POLRMT hypo-succinylated, sustaining mitochondrial respiration and driving leukemia progression. Succinyl-CoA thus functions as a key metabolic signal bridging mitochondrial metabolism and transcription in both leukemia and solid tumors. TFAM, the packaging factor that recruits POLRMT to promoters, is itself phosphorylated, acetylated, and — most recently — arginine-methylated at position 82 by PRMT5, a modification essential for DNA binding and mitochondrial genome integrity. Loss of PRMT5 leaves breast carcinoma cells vulnerable to mitochondrial DNA damage and oxidative stress, and several PRMT5 inhibitors are already in clinical trials, raising the prospect of attacking tumor bioenergetics through the transcription apparatus itself.

Downstream, RNA processing and ribosome assembly consume enormous metabolic resources. The 12S and 16S ribosomal RNAs of the mitoribosome are studded with SAM-dependent methylation marks: TFB1M dimethylates the 3′ end of 12S rRNA to stabilize the small subunit, NSUN4 methylates cytosine 911, METTL15 installs N4-methylcytidine at position 839, and TRMT61B places N1-methyladenosine at position 947 of 16S rRNA, a modification conserved across all vertebrates that stabilizes local ribosome structure. Strikingly, when SAM is depleted, unprocessed pre-rRNA accumulates and mitoribosome assembly grinds to a halt. The same SAM pool feeds transfer RNA modifications, including the taurine-and-GTP-dependent wobble modification 5-taurinomethyluridine installed by GTPBP3 and MTO1, which is essential for translation fidelity — and, notably, MTO1 upregulation in melanoma sustains oxidative phosphorylation and confers resistance to vemurafenib. The dioxygenase ALKBH7, which depends on alpha-ketoglutarate and oxygen to erase methylation marks that otherwise delay transfer RNA maturation, adds another metabolite-gated checkpoint to the pipeline.

At the level of protein synthesis, the review highlights an increasingly granular view of mitoribosome regulation. Human mitoribosomes contain three iron-sulfur clusters installed by GLRX5 and BOLA3, enzymes with prognostic value in bladder cancer and lung adenocarcinoma, while METTL17 carries a [4Fe-4S] cluster that confers redox-sensing activity to protein synthesis. Lipid metabolism matters too: cardiolipin, enriched in cristae membranes where mitochondrial protein synthesis is spatially confined, promotes the inner-membrane docking of ribosomes, and the remodeling enzyme tafazzin maintains the membrane curvature this requires. Perhaps the most striking recent discovery is lactylation — the attachment of lactate-derived lactyl groups to proteins — now documented on TFAM and multiple ribosomal proteins in clinical tumor tissues, and linked to chemoresistance and metastasis in breast, kidney and lung cancers. Lactate, once dismissed as waste, is actively consumed by mitochondria as fuel and now appears to write epigenetic marks on the very machinery that builds the respiratory chain.

The mitochondrial genome also hides a second layer of coding information. Beyond its thirteen canonical proteins, it produces microproteins with potent biological activity. Humanin, a 24-amino-acid peptide, suppresses apoptosis by interfering with Bax activation; it is elevated in the serum of breast cancer patients and accelerates tumor growth, lung metastasis, glioblastoma invasion and temozolomide resistance in experimental models. MOTS-c, a 16-amino-acid peptide from the 12S rRNA open reading frame, activates AMPK and shows context-dependent effects — circulating levels rise in prostatic precancerous lesions and hepatocellular carcinoma yet fall in adrenal tumors, while in liver cancer MOTS-c promotes apoptosis under hypoxia and suppresses tumor growth. Additional peptides such as the SHLP family, SHMOOSE and CYTB-187AA underscore that the mitochondrial central dogma generates unanticipated regulators whose roles in cancer are only beginning to be mapped.

The translational payoff is substantial. The allosteric POLRMT inhibitor IMT1B blocks mitochondrial transcription with minimal toxicity in normal tissues and suppresses leukemia, endometrial carcinoma and other tumors in preclinical models. The thymidine analog alovudine inhibits POLG, impairing oxidative phosphorylation in acute myeloid leukemia, while small-molecule activators such as PZL-A allosterically restore mutant polymerase activity. FDA-approved antibiotics quinupristin and dalfopristin inhibit mitochondrial translation and reduce glioblastoma stem cell clonogenicity, and linezolid suppresses T cell metabolism through the same route, with hematological toxicities limiting its use. Inhibition of dihydroorotate dehydrogenase by ML390 starves leukemia cells of pyrimidines needed for mitochondrial biogenesis, and the iron chelator deferoxamine disrupts OXPHOS super-complexes in breast cancer with encouraging selectivity. Genome-wide sequencing has also revealed that colorectal cancer mitochondrial DNA mutations carry prognostic weight, with MT-CYB mutations significantly correlating with poor patient survival.

Perhaps the most futuristic front is mitochondrial genome editing itself. DddA-derived cytosine base editors and TALE-linked deaminases now allow precise CG-to-TA and A-to-G conversions in mitochondrial DNA, and adeno-associated virus vectors have delivered these editors to post-mitotic mouse tissue, while engineered mitoARCUS nucleases have cleared mutant mitochondrial DNA systemically in animal models. Off-target nuclear editing — reported at rates up to 17.5 percent at some sites — and unintended heteroplasmy shifts remain serious concerns, spurring strategies such as nuclear export signals, strand-selective editors like CyDENT, and tumor-specific promoters to restrict editing to cancer cells. The review’s authors close with a call to integrate high-resolution structural biology, single-cell metabolomics and in vivo lineage tracing to decode the spatiotemporal choreography of mitochondrial gene expression. If they are right, the organelle’s second genome — long overshadowed by the nucleus — may prove to be one of the most exploitable weaknesses a tumor carries.

evolutionary backdrop helps explain why this control system is so intricate. Mitochondria descend from a free-living prokaryotic ancestor engulfed more than 1.45 billion years ago, and the long history of metabolic trade-offs with the host cell left the organelle semi-autonomous: most of its roughly 1,500 proteins are nuclear-encoded, yet the thirteen genes retained in the compact circular genome encode core respiratory chain subunits whose expression must be tuned to local energy demand. Because mtDNA copy number varies naturally across tissues, its dysregulation is directly tied to cancer risk, and tumor cells dynamically adjust both genome abundance and gene output to match proliferative and metastatic needs.

Structural organization adds another layer of control. The mitochondrial genome packs into nucleoids within the matrix, with most protein- and rRNA-coding regions flanked by transfer RNA genes, and regulatory marks such as 5-methylcytosine concentrate in the displacement loop, the non-coding region where replication and transcription originate. Recent structural work has also complicated the classic picture of the replicase: POLG2 can contact DNA independently of POLG without altering polymerase activity, hinting at versatile functions beyond processive elongation.

Methodological caveats deserve emphasis for readers weighing the evidence. Detecting low-frequency mitochondrial modifications demands careful technique; antibody-based capture, bisulfite conversion, isotope labelling, HPLC–mass spectrometry and next-generation sequencing each carry distinct biases, and incomplete light-strand coverage can distort tumor measurements. As optimised protocols spread and quantitative data accumulate across tumor types, the field should be better placed to separate genuine metabolic regulation from technical noise, sharpening the therapeutic opportunities this review maps out.

Subject of Research: Metabolic regulation of the mitochondrial central dogma in cancer

Article Title: Exploring mitochondrial central dogma in cancer from a metabolic perspective

Article References: Zhang, S., Han, B., Chen, L., Chen, L., Wang, T., Lin, M., Liu, J., & Wang, Y. (2026). Exploring mitochondrial central dogma in cancer from a metabolic perspective. Clinical Cancer Bulletin, 5(1), Article 19. https://doi.org/10.1007/s44272-026-00071-5

Image Credits: AI Generated

DOI: 10.1007/s44272-026-00071-5

Keywords: mitochondria, mitochondrial DNA, mtDNA replication, POLRMT, TFAM, mitoribosome, RNA modifications, lactylation, mitochondrial translation, humanin, MOTS-c, mitochondrial genome editing