  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 mitochondria, is increasingly being recognised 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 (we term
`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 recognised role in contributing to cellular
heterogeneity, highlights the need for future single-cell mitochondrial
measurements in the context of cellular noise studies.
