Tools and approaches for analyzing the role of mitochondria in health, development and disease using human cerebral organoids

Mitochondria are cellular organelles involved in generating energy to power various processes in the cell. Although the pivotal role of mitochondria in neurogenesis was demonstrated (first in animal models), very little is known about their role in human embryonic neurodevelopment and its pathology. In this respect human-induced pluripotent stem cells (hiPSC)-derived cerebral organoids provide a tractable, alternative model system of the early neural development and disease that is responsive to pharmacological and genetic manipulations, not possible to apply in humans. Although the involvement of mitochondria in the pathogenesis and progression of neurodegenerative diseases and brain dysfunction has been demonstrated, the precise role they play in cell life and death remains unknown, compromising the development of new mitochondria-targeted approaches to treat human diseases. The cerebral organoid model of neurogenesis and disease in vitro provides an unprecedented opportunity to answer some of the most fundamental questions about mitochondrial function in early human neurodevelopment and neural pathology. Largely an unexplored territory due to the lack of tools and approaches, this review focuses on recent technological advancements in fluorescent and molecular tools, imaging systems, and computational approaches for quantitative and qualitative analyses of mitochondrial structure and function in three-dimensional cellular assemblies-cerebral organoids. Future developments in this direction will further facilitate our understanding of the important role or mitochondrial dynamics and energy requirements during early embryonic development. This in turn will provide a further understanding of how dysfunctional mitochondria contribute to disease processes.