Not all mitochondrial DNAs are made equal and the nucleus knows it

Abstract

The oxidative phosphorylation (OXPHOS) system is the only structure in animal cells with components encoded by two genomes, maternally transmitted mitochondrial DNA (mtDNA), and biparentally transmitted nuclear DNA (nDNA). MtDNA-encoded genes have to physically assemble with their counterparts encoded in the nucleus to build together the functional respiratory complexes. Therefore, structural and functional matching requirements between the protein subunits of these molecular complexes are rigorous. The crosstalk between nDNA and mtDNA needs to overcome some challenges, as the nuclear-encoded factors have to be imported into the mitochondria in a correct quantity and match the high number of organelles and genomes per mitochondria that encode and synthesize their own components locally. The cell is able to sense the mito-nuclear match through changes in the activity of the OXPHOS system, modulation of the mitochondrial biogenesis, or reactive oxygen species production. This implies that a complex signaling cascade should optimize OXPHOS performance to the cellular-specific requirements, which will depend on cell type, environmental conditions, and life stage. Therefore, the mitochondria would function as a cellular metabolic information hub integrating critical information that would feedback the nucleus for it to respond accordingly. Here, we review the current understanding of the complex interaction between mtDNA and nDNA.

Keywords: cytoplasmic communication; intergenomic coadaptation; mito-nuclear interactions; mitochondrial DNA; mitochondrial haplotypes; nucleo-mitochondrial mismatch; respiratory complexes and supercomplexes; retrograde responses.

FIGURE 1

OXPHOS System: Overview of nuclear and mitochondrial‐encoded proteins. In color, mitochondrial‐encoded peptides (Complex I: mt‐ND1, mt‐ND2, mt‐ND3, mt‐ND4, mt‐ND4L, mt‐ND5 and mt‐ND6; Complex III: mt‐CYB; Complex IV: mt‐CO1, mt‐CO2, mt‐CO3; ATP Synthase (Complex V): mt‐ATP6 and mt‐ATP8). In grey, all the nuclear‐encoded subunits

FIGURE 2

(a) The consequences of nucleo‐mitochondrial mismatch on basal ROS production in culture cells ⁵⁹ and animal models. ⁶⁷ (b) Mitohormesis contributes to healthy ageing. An increase in non‐pathological basal mtROS levels induce regular mild mitochondrial stress, priming the mitochondrial adaptive response to elevated levels of cellular stress. BL/6NZB conplastic mice present a delay in the hallmarks of aging detailed in the schematic

FIGURE 3

Summary of the proposed regulatory signals and pathways involved in the integration of the OXPHOS genetic complexity, retrograde response, and cytoplasmic communication

FIGURE 4

Heteroplasmic mouse models harboring in the same cytoplasm, different non‐pathological mtDNA variants‐haplotypes. MtDNA preference is cell‐type‐specific and not tissue‐specific. Also, the metabolic differentiation program determines the preferred mtDNA haplotype and the mtDNA segregation is driven by functional selection and strongly modulated by the crosstalk between the nucleus and mitochondria