Metabolites with a message: impacts on epigenetics and implications for epimetabopathies

Once identified primarily as a bioenergetic organelle, the mitochondrion has now emerged as a pivotal signalling hub that communicates with the nucleus to shape cellular fate. It integrates the cell's metabolic state with transcriptional and epigenetic programs, tweaking gene expression. Mitochondrial metabolites serve as regulators of cellular physiology, functioning as important signalling intermediates and modulating enzymes involved in epigenetic modifications. In parallel, nuclear transcriptional programs govern mitochondrial biogenesis, dynamics and quality control to preserve metabolic homeostasis under stress. Moreover, circulating metabolites can function as systemic messengers coordinating interorgan crosstalk and immune responses. Perturbations in this dynamic reciprocity can rewire the cellular script and spiral into "epimetabopathies", where metabolic-epigenetic conflicts ignite pathological conditions. This review discusses how mitochondria-nucleus crosstalk coordinates genome surveillance, metabolite-driven epigenetic regulation and systemic metabolic signalling. It further offers an overview of epimetabopathies with potential implications for future diagnostics and therapeutics.