Brain organoid as a model to study the role of mitochondria in neurodevelopmental disorders: achievements and weaknesses Provisionally Accepted

Raquel Coronel-López¹ Enrique García-Moreno² Emilio Siendones-Castillo² María J. Barrero³ Beatriz Martinez-Delgado³ Carlos Santos Ocana² Isabel Liste¹ Maria V. Cascajo-Almenara^4*

• ¹Chronic Diseases Research Functional Unit, Carlos III Health Institute (ISCIII), Spain
• ²Andalusian Center for Development Biology, Spanish National Research Council (CSIC), Spain
• ³Rare Diseases Research Institute, Carlos III Health Institute (ISCIII), Spain
• ⁴Andalusian Center of Developmental Biology, and CIBERER, National Institute of Health Carlos III (ISCIII), Pablo de Olavide University-CSIC-JA, Spain

Mitochondrial diseases are a group of severe pathologies that cause complex neurodegenerative disorders for which, in most cases, no therapy or treatment is available. These organelles are critical regulators of both neurogenesis and homeostasis of the neurological system. Consequently, mitochondrial damage or dysfunction can occur as a cause or consequence of neurodevelopmental or neurodegenerative diseases. As genetic knowledge of neurodevelopmental disorders advances, associations have been identified between genes that encode mitochondrial proteins and neurological symptoms, such as neuropathy, encephalomyopathy, ataxia, seizures, and developmental delays, among others. Understanding how mitochondrial dysfunction can alter these processes is essential in researching rare diseases.Three-dimensional (3D) cell cultures, which self-assemble to form specialized structures composed of different cell types, represent an accessible manner to model organogenesis and neurodevelopmental disorders. In particular, brain organoids are revolutionizing the study of mitochondrial-based neurological diseases since they are organ-specific and model-generated from a patient's cell, thereby overcoming some of the limitations of traditional animal and cell models. In this review, we have collected which neurological structures and functions recapitulate in the different types of reported brain organoids, focusing on those generated as models of mitochondrial diseases. In addition to advancements in the generation of brain organoids, techniques, and approaches for studying neuronal structures and physiology, drug screening and drug repositioning studies performed in brain organoids with mitochondrial damage and neurodevelopmental disorders have also been reviewed. This scope review will summarize the evidence on limitations in studying the function and dynamics of mitochondria in brain organoids.