Abstract
ABSTRACTMitochondria are signaling hubs responsible for the generation of energy through oxidative phosphorylation, the production of key metabolites that serve the bioenergetic and biosynthetic needs of the cell, calcium (Ca2+) buffering and the initiation/execution of apoptosis. The ability of mitochondria to coordinate this myriad of functions is achieved through the exquisite regulation of fundamental dynamic properties, including remodeling of the mitochondrial network via fission and fusion, motility and mitophagy. In this Review, we summarize the current understanding of the mechanisms by which these dynamic properties of the mitochondria support mitochondrial function, review their impact on human cortical development and highlight areas in need of further research.
Highlights
Modeling the processes of cortical development is essential for understanding the specific molecular mechanisms involved in human brain development and for elucidating the etiology of many neurological diseases
While the importance of the mitochondria during brain development has long been known, an emerging view emphasizes that mitochondrial homeostasis is tightly regulated during cortical development, and more importantly that mitochondrial morphology and function underlie many of the physiological processes that take place during this fundamental time in human growth
Further adding to potential variations is the compensatory function, mitochondriaderived vesicles (MDVs) and the unfolded protein response (UPRmt) may have Dynamin-related protein 1 (DRP1)-independent approaches to removing damaged parts of the mitochondria without sacrificing the whole organelle (Gitschlag et al, 2016; Lemasters, 2014). It remains to be revealed which pathway predominates in cortical development, as well as how mitophagy is regulated in different cellular compartments and cell types throughout the developing cortex
Summary
Modeling the processes of cortical development is essential for understanding the specific molecular mechanisms involved in human brain development and for elucidating the etiology of many neurological diseases. As individuals with mutations in mitochondrial dynamics genes display severe symptoms of neurodevelopmental regression, atrophy and altered mitochondrial morphologies, leveraging rapidly emerging technologies using human induced pluripotent stem cells (iPSCs) and human embryonic stem cells (hESCs) to model the earliest stages of development and disease may be a powerful tool with which to gain insight into these complex pathways (Arlotta and Pasç a, 2019; Camp et al, 2015; Menacho and Prigione, 2020; Robertson et al, 2020; Romero-Morales et al, 2020) In this Review, we highlight how the dynamic properties of the mitochondria control human cortical development, emphasizing areas of research opportunity and therapeutic need. Perturbations in genes involved in the maintenance of mitochondrial morphology and cristae dynamics have devastating effects on human brain development (Table 1) (AmatiBonneau et al, 2008; Assia Batzir et al, 2019; Bartsakoulia et al, 2018; Benincá et al, 2020; Fahrner et al, 2016; Gerber et al, 2017; Gödiker et al, 2018; Hogarth et al, 2018; Koch et al, 2016; Ladds et al, 2018; Mei et al, 2019; Nasca et al, 2018; Panda et al, 2020; Ryan et al, 2018; Schmid et al, 2019; Shamseldin et al, 2012; Sheffer et al, 2016; Shimizu et al, 2003; Tarailo-Graovac et al, 2019; Development (2021) 148, dev194183. doi:10.1242/dev.194183
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