Tackling mitochondrial diversity in brain function: from animal models to human brain organoids

Mitochondria exhibit high degree of heterogeneity within various tissues, including differences in terms of morphology, quantity, or function. Mitochondria can even vary among distinct sub-compartments of the same cell. Emerging evidence suggest that the molecular diversity of mitochondria can influence the identity and functionality of a given cell type. Human pathologies affecting mitochondria typically cause tissue and cell-type-specific impairment. Mitochondrial diversity could thus play a contributing role not only in physiological cell fate specification but also during pathological disease development. In this review, we discuss the role of mitochondrial diversity in brain function during health and disease. Recent advances in induced pluripotent stem cells (iPSCs) research and the derivation of cerebral organoids could provide novel opportunities to unveil the role of mitochondrial heterogeneity for the function of the human brain. Mitochondrial diversity might be at the bases of the cell-type-specific vulnerability of mitochondrial disorders and may represent an underappreciated target of disease intervention.