<span class="word">Cholesterol <span class="word">in <span class="word"><span class="changedDisabled">Mitochondrial <span class="word"><span class="changedDisabled">Diseases – <span class="word"><span class="changedDisabled">Friend <span class="word">or <span class="word"><span class="changedDisabled">Foe?

Serving as central signalling organelles and hubs of metabolism, mitochondria are essential for cellular homeostasis. Mitochondrial disease can arise from mutations to nuclear or mitochondrial DNA, which result in disruptions to normal mitochondrial function. This generates a suite of rare disorders which are multi-systemic and often fatal. Variable tissue distribution of mitochondria, alongside high heterogeneity in associated phenotype, has resulted in an inadequate understanding and characterisation of mitochondrial disease; ameliorating this is therefore crucial for better clinical management and patient outcomes. Cholesterol dyshomeostasis is a potential pathological hallmark of numerous mitochondrial diseases. Cholesterol is an essential lipid and bioactive compound involved in numerous mitochondrial and cellular processes, including mitochondrial DNA replication and maintenance, mitochondrial membrane integrity, steroidogenesis, and organelle-mitochondria interactions. A growing number of studies have reported perturbations to cholesterol biosynthesis, cholesterol import, and cholesterol ratios, in cell and animal models and individuals with mitochondrial disease, suggesting it could be a unifying feature of these disparate and variable disorders. This review summarises the current experimental evidence of the role of cholesterol dyshomeostasis in mitochondrial disease. It will further discuss reports of statin intolerance, generally attributed to off-target action on mitochondrially important structures, in the context of this evidence. Ultimately, the necessity of further integrative clinical and experimental studies exploring the potential of cholesterol dyshomeostasis as a pathological hallmark of mitochondrial disease will be highlighted.