Mitochondria and the non‐genetic origins of cell‐to‐cell variability: More is different

Abstract

Gene expression activity is heterogeneous in a population of isogenic cells. Identifying the molecular basis of this variability will improve our understanding of phenomena like tumor resistance to drugs, virus infection, or cell fate choice. The complexity of the molecular steps and machines involved in transcription and translation could introduce sources of randomness at many levels, but a common constraint to most of these processes is its energy dependence. In eukaryotic cells, most of this energy is provided by mitochondria. A clonal population of cells may show a large variability in the number and functionality of mitochondria. Here, we discuss how differences in the mitochondrial content of each cell contribute to heterogeneity in gene products. Changes in the amount of mitochondria can also entail drastic alterations of a cell's gene expression program, which ultimately leads to phenotypic diversity. Also watch the Video Abstract.

Mitochondrial levels determine variability in cell death by modulating apoptotic gene expression

“…To assess the impact of mitochondrial levels on transcripts, HeLa cells were sorted in two fractions with high and low levels of mitochondria, and total RNA was deep sequenced. As previously described 17 , 24 , we observed a global scaling of the transcriptome abundance between both subpopulations, where cells in the fraction with high mitochondrial levels contained around three times more RNA than cells in the low fraction (Supplementary Fig. 6 ).…”

Mitophagy plays a central role in mitochondrial ageing

“…We now know that nuclear–mitochondria crosstalk is not only in the nucleus-to-mitochondria direction, via production and import of the vast majority of the proteins necessary to build a mitochondrion and regulation by sirtuins. The retrograde response where mitochondria content and activity regulate nuclear gene expression is also critically important (Guantes et al 2015 , 2016 ). Overall the mitochondria content and quality appear to be important features of the ageing process.…”

Metabolism of Preimplantation Embryo Development

“…L-OPA1 protein functions to regulate the shape of cristae through their interaction with mitochondrial solute carrier protein (SLC25A), independent of its function in the fission/fusion process (Patten et al, 2014). These and other studies strongly suggest that mitochondria do not merely serve a subservient role as a cellular energy factory but plays major roles in sensing and dictating cellular processes that ultimately bring about changes in nuclear gene expression (Guantes, Diaz-Colunga, & Iborra, 2016;Whelan & Zuckerbraun, 2013).…”