Abstract
Cell-to-cell heterogeneity drives a range of (patho)physiologically important phenomena, such as cell fate and chemotherapeutic resistance. The role of metabolism, and particularly of mitochondria, is increasingly being recognized as an important explanatory factor in cell-to-cell heterogeneity. Most eukaryotic cells possess a population of mitochondria, in the sense that mitochondrial DNA (mtDNA) is held in multiple copies per cell, where the sequence of each molecule can vary. Hence, intra-cellular mitochondrial heterogeneity is possible, which can induce inter-cellular mitochondrial heterogeneity, and may drive aspects of cellular noise. In this review, we discuss sources of mitochondrial heterogeneity (variations between mitochondria in the same cell, and mitochondrial variations between supposedly identical cells) from both genetic and non-genetic perspectives, and mitochondrial genotype-phenotype links. We discuss the apparent homeostasis of mtDNA copy number, the observation of pervasive intra-cellular mtDNA mutation (which is termed “microheteroplasmy”), and developments in the understanding of inter-cellular mtDNA mutation (“macroheteroplasmy”). We point to the relationship between mitochondrial supercomplexes, cristal structure, pH, and cardiolipin as a potential amplifier of the mitochondrial genotype-phenotype link. We also discuss mitochondrial membrane potential and networks as sources of mitochondrial heterogeneity, and their influence upon the mitochondrial genome. Finally, we revisit the idea of mitochondrial complementation as a means of dampening mitochondrial genotype-phenotype links in light of recent experimental developments. The diverse sources of mitochondrial heterogeneity, as well as their increasingly recognized role in contributing to cellular heterogeneity, highlights the need for future single-cell mitochondrial measurements in the context of cellular noise studies.
Highlights
Cellular heterogeneity plays central functional roles in a variety of biomedically important phenomena, such as development (Vassar et al, 1993; Chang et al, 2008), virus infection (Snijder et al, 2009), chemotherapeutic resistance (Spencer et al, 2009; Márquez-Jurado et al, 2018), and gene expression in aging (Bahar et al, 2006)
Mitochondrial heterogeneity can occur at various scales
We have focussed on heterogeneity in the mitochondrial population within a cell and inter-cellular heterogeneity of aggregate permitochondrion observables
Summary
Cellular heterogeneity plays central functional roles in a variety of biomedically important phenomena, such as development (Vassar et al, 1993; Chang et al, 2008), virus infection (Snijder et al, 2009), chemotherapeutic resistance (Spencer et al, 2009; Márquez-Jurado et al, 2018), and gene expression in aging (Bahar et al, 2006). Inter-cellular heterogeneity may arise from the intrinsically stochastic nature of cellular processes including gene transcription (Elowitz et al, 2002; Swain et al, 2002), and from “extrinsic” sources such as the cell cycle (Newman et al, 2006) and partitioning noise (Huh and Paulsson, 2011a,b; Johnston and Jones, 2015). Since global transcription rate has diverse implications for cellular function (Raj and van Oudenaarden, 2008), this link provides compelling evidence for the importance of mitochondrial heterogeneity as a contributor to cellular noise. Our discussion is biomedically focussed, so we will emphasize findings in humans and model organisms used to study human disease such as mouse, fly, worm and yeast (the plant kingdom has several unique aspects of mitochondrial heterogeneity, recently reviewed by Johnston, 2018). We provide a necessarily non-exhaustive discussion of recent developments in these topics, and point out potential areas for future development
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