Fig. 3

Obstacles to functional mitochondria-to-nucleus gene transfer. Subsequent steps in the transfer of mitochondrial (mt) genes to the nuclear genomes are indicated with (numbered) grey arrows. Obstacles to transfer are marked by letters (A–H) and arrows (CoRR hypothesis: red; constraints hypothesis: magenta). Genetic material can be transferred from the mitochondria to the nuclei as DNA or cDNA (1) during fission/fusion events, mitochondrial lysis or mitophagy, the transfer process being facilitated by organelle proximity and vacuole formation, protecting DNA fragments from cytoplasmic nucleases. Entrenched mitochondrial gene regulation can be a barrier to transfer. A specific case of regulation of expression by redox sensors and redox response regulators forms the crux of the CoRR hypothesis. Gene transfer in the opposite direction (nucleus-to-mitochondrial genome (2)) is extremely rare (so far, only demonstrated in corals and plants). Upon (c)DNA transfer, integration into a suitable genome locus (B) without disrupting essential genes or causing genome instability has to occur. Some genes will gain mitochondrial targeting signals (orange segments) from other nuclear genes (C) or formed de novo. The newly transferred gene should gain regulatory elements (green dots) enabling efficient expression (D) or be transcribed polycistronically with a nuclear gene. The process of codon optimization might contribute to establishing optimal expression levels of the now nucleus-encoded gene (D). For some organisms, mitochondrial RNA editing/deviations of the genetic code might represent extra obstacles to effective gene transfer (D). Upon successful completion of the steps mentioned, mRNA is synthesized and exported to the cytoplasm (3), where proteins are synthesized (4) on cytosolic ribosomes (olive green circles). Proteins with highly hydrophobic transmembrane domains, >  ~ 120 amino acids (length threshold for proteins to be recognized by the signal recognition particle), would thus be co-translationally miss-targeted to the ER (E). Newly synthesized proteins might be degraded by cytoplasmic peptidases (F) or bind chaperones (5) and be directed to mitochondria. Proteins enter mitochondria using a pre-sequence mediated pathway involving TOM and TIM23 complexes (6), with subsequent cleavage of pre-sequences by mitochondrial processing peptidase (7), or via other mechanisms (8). High protein hydrophobicity might represent a significant barrier to traversing the mitochondrial membranes (G). Following a successful transport into the mitochondria, proteins assume native conformations (9) and in some cases are incorporated into their respective protein complexes (10). Protein complex assembly processes normally involve highly ordered sets of steps, often requiring co-translational incorporation of subunits, potentially representing an additional barrier (H) for functional gene transfer to the nucleus