Germline TFAM levels regulate mitochondrial DNA copy number and mutant heteroplasmy in C. elegans

Abstract

The mitochondrial genome (mtDNA) is packaged into discrete protein-DNA complexes called nucleoids. mtDNA packaging factor TFAM (mitochondrial transcription factor-A) promotes nucleoid compaction and is required for mtDNA replication. Here, we investigate how changing TFAM levels affects mtDNA in the Caenorhabditis elegans germ line. We show that increasing germline TFAM activity boosts mtDNA number and significantly increases the relative proportion of a selfish mtDNA mutant, uaDf5 . We conclude that TFAM levels must be tightly controlled to ensure appropriate mtDNA composition in the germ line.

Multiple distinct evolutionary mechanisms govern the dynamics of selfish mitochondrial genomes

“…The variant uaDf5 is an exemplary model selfish mitochondrial genome, undergoing positive intraorganismal selection at the expense of host fitness. 26,30,32,[34][35][36]38 We expand the understanding of uaDf5 in numerous key ways. Prior studies have found that uaDf5 proliferates not merely in spite of, but at least partly because of, its negative effect on mitochondrial function.…”

“…26,32,34,36,41 Moreover, proteins with a more direct role in mitochondrial biogenesis and mtDNA replication, such as POLG and the mtDNA-associated protein TFAM, or that promote binding of replication machinery to mtDNA, reportedly mediate selfish mtDNA proliferation. 30,32,36 Conversely, genes involved in mitochondrial fission and autophagy reportedly contribute to intra-organismal selection against mutant mtDNA. 34,36,37,39,[58][59][60] Given these findings, we propose that host genotypes and environmental factors, especially those linking physiological stress with mtDNA replication and turnover, will be important determinants of the cooperator-cheater dynamics described here and should be considered in future research.…”

“…Consistent with the conceptual framework of multilevel selection, prior research has uncovered numerous insights into the molecular, physiological, and environmental determinants of the fitness effects of mitochondrial mutations. [29][30][31][32] Many such findings can be credited to the mutant genome uaDf5 in the model species Caenorhabditis elegans. 26,[30][31][32][33][34][35][36][37][38][39] Due to a 3.1-kilobase deletion resulting in the loss of four proteincoding and seven tRNA genes (Fig.…”

“…[29][30][31][32] Many such findings can be credited to the mutant genome uaDf5 in the model species Caenorhabditis elegans. 26,[30][31][32][33][34][35][36][37][38][39] Due to a 3.1-kilobase deletion resulting in the loss of four proteincoding and seven tRNA genes (Fig. 1a), uaDf5 negatively impacts mitochondrial respiration and host fitness.…”

“…6 On one hand, these findings highlight uaDf5 as a valuable model of a biological cheater. On the other hand, a disproportionate fraction of mechanistic insights have come through studying this genome, 18,26,27,29,30,32,34,36,37,39 which challenges the ability to draw broad conclusions. Moreover, although prior studies have implicated diverse mito-nuclear interactions in the selfish propagation of mitochondrial mutations, 26,29,32,34,36,41 as well as substantial variation in their phenotypic effects, 42,43 this work spans multiple species.…”