Mitochondrial Heterogeneity

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.

The Mitochondrial Genome–on Selective Constraints and Signatures at the Organism, Cell, and Single Mitochondrion Levels

“…Accordingly, Ferree et al (2013) showed that knockout of mitophagy factors led to an accumulation of partly dysfunctional, aged mitochondria. Hence, mitochondria within single mammalian cells are frequently not uniform in function (Aryaman et al, 2018), and hence will be under differential selective constraints between cell types, tissues, and cells in the same tissue. Taken together, functional differences in mitochondrial activities are observed not only at the organism level, but also between and within cells.…”

Mitochondrial Network State Scales mtDNA Genetic Dynamics

“…Overall, our simple model consists of 4 species ðW S ; W F ; M S ; M F Þ, 6 independent parameters, and 15 reactions, and captures the central property that mitochondria fragment before degradation (Twig et al 2008). Throughout this work, we define heteroplasmy as the mutant-allele fraction per cell of a mitochondrially encoded variant (Wonnapinij et al 2008;Samuels et al 2010;Aryaman et al 2019):…”

“…Mitochondria exist within a network which dynamically fuses and fragments. Although the function of mitochondrial networks remains an open question (Hoitzing et al 2015), it is often thought that a combination of network dynamics and mitochondrial autophagy (termed mitophagy) act in concert to perform quality control on the mitochondrial population (Twig et al 2008;Aryaman et al 2019;Johnston 2019). Observations of pervasive intramitochondrial mtDNA mutation (Morris et al 2017) and universal heteroplasmy in humans (Payne et al 2012) suggest that the power of this quality control may be limited.…”

Mitochondrial network state scales mtDNA genetic dynamics

“…Overall, our simple model consists of 4 species (W S , W F , M S , M F ), 6 independent parameters and 15 reactions, and captures the central property that mitochondria fragment before degradation (Twig et al, 2008). Throughout this work, we define heteroplasmy as the mutant allele fraction per cell of a mitochondriallyencoded variant (Aryaman et al, 2019;Samuels et al, 2010;Wonnapinij et al, 2008):…”

“…Mitochondria exist within a network which dynamically fuses and fragments. Although the function of mitochondrial networks remains an open question (Hoitzing et al, 2015), it is often thought that a combination of network dynamics and mitochondrial autophagy (termed mitophagy) act in concert to perform quality control on the mitochondrial population (Aryaman et al, 2019;Johnston, 2018;Twig et al, 2008). Observations of pervasive intra-mitochondrial mtDNA mutation (Morris et al, 2017) and universal heteroplasmy in humans (Payne et al, 2012) suggest that the power of this quality control may be limited.…”