Mitochondrial DNA emerges as central regulator of mito-nuclear retrograde signaling, beyond metabolic roles.

Maintaining cellular homeostasis and coordinating adaptive responses to stress relies on dynamic, bidirectional communication between mitochondria, the cytoplasm, and the nucleus, known as mito-nuclear crosstalk. Traditionally, retrograde signaling was seen as a consequence of metabolic or oxidative stress. However, a growing body of evidence suggests mitochondrial DNA (mtDNA) plays a central, active role in orchestrating these critical signaling pathways. Understanding this deeper role of mtDNA is crucial for deciphering complex cellular responses to various stressors and diseases.

This comprehensive review synthesizes current knowledge on mtDNA-driven retrograde signaling, examining both classical and emerging mechanisms. It explores how perturbations in mtDNA integrity, copy number, or expression initiate retrograde responses. The authors discuss the critical roles of mtDNA-derived products, including mitochondrial-derived non-coding RNAs (mt-ncRNAs) and mitochondrial-derived peptides (MDPs), as key messengers. The review also delves into how mtDNA instability, defective repair, and altered mitochondrial dynamics trigger specific signaling cascades.

The review highlights that mtDNA is not merely a genetic blueprint for the electron transport chain but functions as a dynamic signaling hub that actively conveys information about mitochondrial functional status to the nucleus. This communication orchestrates adaptive responses to stress, extending beyond traditional metabolic roles. > Perturbations in mtDNA integrity, copy number, or expression are shown to initiate robust retrograde responses through metabolic rewiring, alterations in redox and calcium signaling, and activation of stress-responsive transcriptional programs. Furthermore, mtDNA-derived products, including mt-ncRNAs and MDPs, are identified as crucial intercellular messengers that shuttle between cellular compartments. These molecules reshape nuclear gene expression and influence cellular and systemic responses to stress, participating in diverse processes ranging from mitochondrial biogenesis and quality control to innate immune activation and epigenetic regulation, underscoring the multifaceted role of the mitochondrial genome in cellular communication.