Mitochondrial dynamics and function in neural differentiation: a systematic review

Mitochondrial function has emerged as a critical regulator of neural differentiation, yet a comprehensive understanding of its diverse roles and temporal dynamics remains elusive. This systematic review synthesizes current evidence regarding mitochondrial contributions to neural stem cell differentiation and their implications for neurodevelopmental disorders.

A systematic search was conducted across PubMed, Web of Science, and Scopus databases from inception to January 2025. Studies investigating mitochondrial properties during neural differentiation were included. Data extraction focused on temporal changes in mitochondrial function, molecular mechanisms, and pathological implications. Quality assessment was performed using modified SYRCLE criteria.

Analysis of 50 studies revealed distinct temporal patterns of mitochondrial regulation during neural differentiation. Early stages (days 0-3) showed predominant mitochondrial fragmentation and elevated ROS levels, while intermediate stages (days 4-7) demonstrated a shift toward oxidative phosphorylation with increased fusion events. Late-stage differentiation (beyond day 7) exhibited mature mitochondrial networks and stable bioenergetic profiles. The key molecular mechanisms included calcium signaling, Wnt/β-catenin pathway activation, and dynamic regulation of fusion/fission proteins. Mitochondrial dysfunction was consistently associated with impaired neural differentiation across multiple neurodevelopmental disorders.

Mitochondrial regulation of neural differentiation involves stage-specific changes in morphology, metabolism, and signaling functions. The identification of key molecular pathways provides promising therapeutic targets for neurodevelopmental disorders. Future research should focus on standardizing assessment methods, understanding tissue-specific regulation, and developing targeted interventions for clinical applications. These findings highlight the therapeutic potential of mitochondrial-targeted approaches in treating neurodevelopmental disorders and advancing regenerative medicine strategies.