Small mitochondrial RNAs as mediators of nuclear gene regulation, and potential implications for human health

Bioessays. 2021 Jun;43(6):e2000265. doi: 10.1002/bies.202000265. Epub 2021 Mar 24.


Much research has focused on the effects of pathogenic mitochondrial mutations on health. Notwithstanding, the mechanisms regulating the link between these mutations and their effects remain elusive in several cases. Here, we propose that certain mitochondrial mutations may disrupt function of a set of mitochondrial-transcribed small RNAs, perturbing communication between mitochondria and nucleus, leading to disease. Our hypothesis synthesises two lines of supporting evidence. First, several mitochondrial mutations cannot be directly linked to effects on energy production or protein synthesis. Second, emerging studies have described the existence of small RNAs encoded by the mitochondria and proposed their involvement in RNA interference. We present a roadmap to testing this hypothesis.

Keywords: RNA interference; mitochondria; mitochondrial disease; mtDNA mutation; small RNAs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Nucleus* / genetics
  • Cell Nucleus* / metabolism
  • DNA, Mitochondrial / metabolism
  • Gene Expression Regulation
  • Humans
  • Mitochondria* / genetics
  • Mutation
  • RNA / genetics
  • RNA / metabolism
  • RNA, Mitochondrial / genetics


  • DNA, Mitochondrial
  • RNA, Mitochondrial
  • RNA