Methionine synthase reductase regulates heterochromatin independently of methionine synthesis through mitochondrial homeostasis

Metabolic enzymes can influence chromatin organization by modulating the availability of key metabolites, yet how specific metabolic reactions affect chromatin function remains poorly understood. Here, we show that in Caenorhabditis elegans, the methionine-cycle enzyme methionine synthase reductase (MTRR-1/MSR) regulates heterochromatin independently of methionine synthesis. Loss of MTRR-1, but not of the methionine synthase METR-1/MS, specifically reduces heterochromatic histone methylation, derepresses repetitive elements, and causes developmental delay. Multi-omics profiling revealed that <i>mtrr-1</i> mutants activate transcriptional programs associated with mitochondrial stress and accumulate long-chain acylcarnitines, indicating disrupted mitochondrial homeostasis. Functional assays confirmed altered mitochondrial respiration in <i>mtrr-1</i> mutants, while direct perturbation of mitochondrial function was sufficient to induce heterochromatin defects. Together, our results reveal a previously unrecognized mitochondria-to-chromatin axis controlled by the methionine-cycle enzyme MTRR-1/MSR.