A new member in the Argonaute crew: the mt-miRNAs

Abstract

1Mutations within the mitochondrial genome have been linked to many diverse phenotypes. 2 Moreover, the effects of these mutations have been shown to differ across sexes and environments. 3 The mechanisms that explain the manifold array of mitochondrial genotypic effects on organismal 4 function, and their context-dependency, have however remained a mystery. Here, we present 5 evidence that mitochondria are involved in nuclear gene regulation via RNA interference; 6 transcribing mitochondrial (mt-)miRNAs that may repress the transcription of nuclear genes that 7 previously had no known involvement in mitochondrial function. Our findings uncover a new 8 mechanism by which mitochondria may shape the expression of animal life-histories and health 9 components; implying that the influence of the mitochondria in regulating organismal function 10 extends well beyond the process of energy production. 11 Introduction 12 Interest in mitochondrial biology is on the rise, with a growing number of studies 13 highlighting the complex role of the mitochondria in cell regulation (Picard, Wallace, and Burelle 14 2016; Sloan et al. 2018; Sprenger and Langer 2019). Among these, numerous studies have found 15 that sequence variation in the mitochondrial DNA (mtDNA) can affect the expression of a range 16 of life-history and health related traits, from fertility, to longevity and thermal tolerance (Lajbner 17 et al. 2018; Camus et al. 2017; Rand, Fry, and Sheldahl 2006; Song and Lewis 2008; Yee, Sutton, 18 and Dowling 2013; James and Ballard 2003). Furthermore, while it is well known that the mtDNA 19 can harbour loss-of-function mutations conferring mitochondrial disease in humans (Wallace 20 2018), emerging studies implicate mtDNA mutations in a range of other late-onset diseases not 21 previously linked to mitochondrial function (Hudson et al. 2014). For example, Hopkins et al. 22 (2017) recently reported an association between the frequency and type of mtDNA mutations and aggressiveness of prostate cancer. Furthermore, the phenotypic effects of these mtDNA mutations 1 appear to be routinely moderated by the nuclear genetic background alongside which the mtDNA 2 mutations are co-expressed (Hill et al. 2018), suggesting a broad role for intergenomic regulation 3 ("mitonuclear communication") involving exchange of proteins, metabolites and genetic products 4 between genomes (Wu et al. 2019; Moriyama, Koshiba, and Ichinohe 2019; Zhu, Ingelmo, and 5 Rand 2014). The mechanistic basis of the molecular interactions that underpin mitonuclear 6 regulation of cellular and organismal function, however, remains elusive. 7 In 2019, Kopinski et al. provided new insights into how the mitochondria communicate 8 with the nucleus, reporting a key role for mitochondrial metabolites and subcellular redox levels. 9The authors found that variation in the level of intracellular mtDNA heteroplasmy (i.e. the 10 frequency of normal to mutant mtDNA molecules) modulates mitochondrial metabolites, 11 influencing the abundance of substrate necessary for...

Relaxed selection on male mitochondrial genes in DUI bivalves eases the need for mitonuclear coevolution

“…Transcribed small RNAs from the M mt genome may also affect expression of nuclear‐encoded genes as part of sex determination in DUI species (Pozzi et al, 2017). Recent work suggests that such mt‐encoded small RNAs (termed “smithRNAs” or “mt‐miRNAs”) may be ubiquitous across animals (Pozzi & Dowling, 2019, 2020). Our results complement these findings and suggest that evolution of M mt OXPHOS genes may also result in altered mitonuclear interactions, possibly through altering OXPHOS function (see below).…”

The origin of RNA interference: Adaptive or neutral evolution?

“…In the thale cress Arabidopsis thaliana , 25% of the transfer RNA (tRNA)-derived sRNAs that immunoprecipitate with Argonaute-1 come from plastid tRNAs, suggesting the presence of a retrograde signaling pathway [ 151 ]. In humans, a mitochondrial sRNA derived from the polycistronic mitochondrial RNA can interact with Argonaute-2 and possibly target the 3′-UTR region of CFLAR [ 152 ]. The intracellular pathogen Mycobacterium marinum produces an sRNA where the secondary structure is processed like an miRNA by the host cells, and which interacts with the RNA-induced silencing complex [ 153 ].…”