The Mitochondrial Genome–on Selective Constraints and Signatures at the Organism, Cell, and Single Mitochondrion Levels

Abstract

Natural selection acts on the phenotype. Therefore, many mistakenly expect to observe its signatures only in the organism, while overlooking its impact on tissues, cells and subcellular compartments. This is particularly crucial in the case of the mitochondrial genome (mtDNA), which, unlike the nucleus, resides in multiple cellular copies that may vary in sequence (heteroplasmy) and quantity among tissues. Since the mitochondrion is a hub for cellular metabolism, ATP production, and additional activities such as nucleotide biosynthesis and apoptosis, mitochondrial dysfunction leads to both tissue-specific and systemic disorders. Therefore, strong selective pressures act to maintain mitochondrial function via removal of deleterious mutations via purifying (negative) selection. In parallel, selection also acts on the mitochondrion to allow adaptation of cells and organisms to new environments and physiological conditions (positive selection). Nevertheless, unlike the nuclear genetic information, the mitochondrial genetic system incorporates closely interacting bi-genomic factors (i.e., encoded by the nuclear and mitochondrial genomes). This is further complicated by the order of magnitude higher mutation rate of the vertebrate mtDNA as compared to the nuclear genome. Such mutation rate difference generates a generous mtDNA mutational landscape for selection to act, but also requires tight mito-nuclear co-evolution to maintain mitochondrial activities. In this essay we will consider the unique mitochondrial signatures of natural selection at the organism, tissue, cell, and single mitochondrion levels.

Ciliate mitoribosome illuminates evolutionary steps of mitochondrial translation

“…The involvement of two genomes to produce a functional and stable protein further indicates an evolutionary link between genetic drift and mitochondrial translation. Our experimental finding therefore illustrates the requirement of tight mito-nuclear coevolution to maintain mitochondrial activities ( Shtolz and Mishmar, 2019 ; Mishmar, 2020 ).…”

Age-related accumulation of de novo mitochondrial mutations in mammalian oocytes and somatic tissues

“…Because of the very low frequency of these mutations in contrast to the high copy number of mtDNA (hundreds to around 200,000 copies, with an average of 1–10 mtDNA copies per mitochondrion in mature oocytes [ 16 , 82 ]), mutations in one or a few mtDNA molecules are not expected to have noticeable functional consequences for a cell compared with mutations in the nuclear genome. However, at a single-mitochondrion level, they might have a functional impact ([ 83 ], reviewed in [ 84 ]). In contrast, negative selection was demonstrated for high-allele-frequency mtDNA mutations in the mouse germline (reviewed in [ 85 ]), and it was suggested that purifying selection does not act directly on oocytes but rather on cells during postimplantation development [ 86 ].…”

Genomic Landscape of the Mitochondrial Genome in the United Arab Emirates Native Population

“…Almost in all cases, nuclear DNA is used to describe the signature of selection, while ignoring its effect on the tissue, cells, and subcellular compartments. This is very crucial for mitogenome, which in contrast to the nucleus, serves as a powerhouse for the cell and are present in multiple copies in the cytoplasm that may vary in sequence (heteroplasmy) and quantity among tissues [ 20 ]. Each mitochondrion is maternally inherited and codes for enzymes that are mainly involved in cellular bioenergetics [ 21 ].…”

“…Each mitochondrion is maternally inherited and codes for enzymes that are mainly involved in cellular bioenergetics [ 21 ]. As it is a vital compartment for the generation of cellular metabolism, including ATP production, nucleotide biosynthesis, and other activities, any dysfunction will lead to tissue and systemic disorders [ 20 ]. Therefore, strong purifying negative selection acts to remove deleterious mutations, and in parallel, positive selection acts on the mitochondria to promote adaptation of cells, and in return the whole organism, to environmental and physiological changes [ 20 , 22 , 23 ].…”