Metabolic regulation of mitochondrial DNA (mtDNA) homeostasis.

Mitochondria are central hubs of cellular metabolism that harbor their own genome (mtDNA), whose maintenance is essential for both cellular and organismal homeostasis. Unlike nuclear DNA, mtDNA replicates continuously throughout the cell cycle, rendering it particularly sensitive to changes in metabolic state. Emerging evidence indicates that mtDNA homeostasis is not governed solely by dedicated replication factors but is tightly coupled to cellular metabolism. In this review, we discuss how metabolic networks shape mtDNA maintenance through three interconnected layers: mitochondrial nucleotide pools, metabolic control of the replication machinery, and stress-response pathways. This conceptual framework underscores the direct role of metabolic state in governing mtDNA replication, stability, and quality control, with significant implications for mitochondrial disease and therapeutic strategies.