Mitochondria-Nuclear Crosstalk: Orchestrating mtDNA Maintenance

Abstract

The mitochondria (mt) and nucleus engage in a dynamic bidirectional communication to maintain cellular homeostasis, regulating energy production, stress response, and cell fate. Anterograde signaling directs mt function, while retrograde signaling conveys metabolic and stress-related changes from mt to the nucleus. Central to this crosstalk is mitochondrial DNA (mtDNA), which encodes key oxidative phosphorylation components. MtDNA integrity is preserved through quality control mechanisms, including fusion and fission dynamics, mitophagy, and nuclear-encoded DNA repair. Disruption in these pathways contributes to mt dysfunction, oxidative stress, and genetic instability-hallmarks of aging and diseases. Additionally, redox signaling and NAD+ homeostasis integrate mt and nuclear responses, modulating transcriptional programs that support mt biogenesis and stress adaptation. This review explores the molecular mechanisms coordinating mito-nuclear interactions, emphasizing their role in maintaining mtDNA integrity and cellular equilibrium. Understanding these processes provides insights into how mt dysfunction drives aging and disease, paving the way for targeted therapeutic strategies.

Keywords: anterograde and retrograde signaling; cellular homeostasis; mitochondrial biogenesis; mitochondrial dynamics; mtDNA maintenance, mitochondrial‐nuclear communication; redox signaling.

FIGURE 1

Bidirectional mito‐nuclear communication in mtDNA maintenance. Mt stress signals regulate mtDNA repair and biogenesis through retrograde and anterograde signaling. Two pathways coordinate this response. Oxidative damage‐driven pathway: mtDNA lesions caused by ROS activate PARP1, APE1, and RAD51, which are recruited to damaged mtDNA sites, promoting base excision repair (BER) and homologous recombination. The second pathway, the DNA stress pathway, mtDNA instability or replication stress triggers mt dysfunction, generating secondary ROS which initiate p38, AMPK, and CAMKII transcription through retrograde signaling and subsequent phosphorylation of PGC‐1α, enhancing its co‐activator function to promote transcription of NRF‐1/2 and ERR. This cascade drives the anterograde response of expression of TFAM, OGG1, and NTH1, which then mediates mt DNA repair and replication.

FIGURE 2

Mitochondrial dynamics and quality control mechanisms. (a) Mitophagy PINK1/Parkin‐independent pathway, where mitophagy receptors such as NIX, FUNDC1, and BNIP3 facilitate mitochondrial degradation by directly interacting with LC3 on the forming autophagosome, leading to lysosomal degradation. Phosphorylation events regulate receptor activation. (b) Mitophagy‐PINK1‐Parkin dependent. Mitophagy selectively removes damaged mt to maintain mt quality. Upon mt damage, PTEN‐induced kinase 1 (Pink1) accumulates on the outer membrane, recruiting E3 ubiquitin ligase Parkin, which ubiquitinates mt surface proteins. These ubiquitinated mt are recognized by autophagic receptors, sequestered into phagophores, and enclosed in autophagosomes. Fusion with lysosomes enables enzymatic degradation and recycling of mt components, preserving cellular homeostasis.

FIGURE 3

Mt DNA maintenance and mt‐nuclear communication in redox regulation. (a) mt stress activates signaling pathways, including AMPK, SIRT, P38 MAPK, and Akt, which regulate the acetylation (AC) and phosphorylation of PGC‐1α. PGC‐1α, in conjunction with NRF1/2, promotes the expression of TFAM, a key mt transcription factor. TFAM is imported into mt, where it regulates mtDNA transcription, replication, and maintenance. (b) Mt OXPHOS generates ROS, which can lead to mtDNA mutations, deletions, and loss of genome integrity. In response, mt send retrograde signals to the nucleus, modulating gene expression to mitigate damage. In turn, the nucleus initiates anterograde signals, such as the upregulation of antioxidants, to protect the mt and maintain cellular homeostasis.