Cell identity and nucleo-mitochondrial genetic context modulate OXPHOS performance and determine somatic heteroplasmy dynamics.

Heteroplasmy, multiple variants of mitochondrial DNA (mtDNA) in the same cytoplasm, may be naturally generated by mutations but is counteracted by a genetic mtDNA bottleneck during oocyte development. Engineered heteroplasmic mice with nonpathological mtDNA variants reveal a nonrandom tissue-specific mtDNA segregation pattern, with few tissues that do not show segregation. The driving force for this dynamic complex pattern has remained unexplained for decades, challenging our understanding of this fundamental biological problem and hindering clinical planning for inherited diseases. Here, we demonstrate that the nonrandom mtDNA segregation is an intracellular process based on organelle selection. This cell type-specific decision arises jointly from the impact of mtDNA haplotypes on the oxidative phosphorylation (OXPHOS) system and the cell metabolic requirements and is strongly sensitive to the nuclear context and to environmental cues.This study was supported by MINECO SAF2015-65633-R to JAE, SAF2016-78114-R to J.P.B. and SAF2017-84494-C2-1-R to J.R.-C. G.S. thanks MINECO-FEDER SAF2016-79126-R and Comunidad de Madrid IMMUNOTHERCAN-CM B2017/BMD-3733. N.S.J. thanks EP/N014529/1. CIBERFES (CB16/10/00282) to J.P.B. and J.A.E., and H2020 European Commission (BatCure grant 666918) to J.P.B. A.V.L.-V. was supported by SOFPI-fellowship from the MINECO. V.C. is supported by the UK Medical Research Council, Cancer Research UK (CRUK) (C399/A2291), and the Oxford Biomedical Research Centre. I.G.J. thanks the European Research Council (ERC- No. 805046-EvoConBiO). The CNIC is supported by MINECO and Pro-CNIC Foundation and is a SO-MINECO (award SEV-2015-0505). CIC biomaGUNE is supported by the Maria de Maeztu Units of Excellence Program from the Spanish State Research Agency (grant no. MDM-2017-0720), ELKARTEK Program (grant no. KK-2019/bmG19), and BBVA Foundation (Ayudas a Equipos de investigación científica Biomedicina 2018)S