Progressive mitochondrial and autophagic dysfunction during RGC development driven by a LHON-associated mitochondrial...

Area of Science:

• Genetics and Molecular Biology
• Neuroscience
• Cell Biology

Background:

• Leber's hereditary optic neuropathy (LHON) is a genetic eye disease caused by mitochondrial DNA (mtDNA) mutations, leading to retinal ganglion cell (RGC) degeneration.
• Previous research identified the MT-TT 15927G>A mutation's impact on tRNA function and mitochondrial dysfunction, but lacked disease models for tissue-specific studies.
• The absence of suitable animal and cell models has hindered understanding of LHON pathophysiology and tissue-specific effects.

Purpose of the Study:

• To establish and characterize a cellular model of LHON using induced pluripotent stem cells (iPSCs) derived from a patient carrying the m.15927G>A mutation.
• To investigate mitochondrial dysfunction and autophagy/mitophagy defects in RGC-like cells at various differentiation stages.
• To provide insights into LHON pathogenesis and create a model for therapeutic development.

Main Methods:

• Generation of RGC-like cells from iPSCs of a Chinese family member with the m.15927G>A mutation and a control subject.
• Assessment of mitochondrial dynamics, mitochondrial dysfunction, autophagy, and mitophagy at iPSC, neural progenitor cell (NPC), and RGC-like cell stages.
• Analysis of neurite length, reactive oxygen species (ROS) production, and mitochondrial membrane potential in RGC-like cells.

Main Results:

• Mutant iPSCs and NPCs exhibited abnormal mitochondrial dynamics, dysfunction, and impaired autophagy/mitophagy.
• LHON-model RGC-like cells displayed shorter neurites, imbalanced mitochondrial dynamics, elevated ROS, reduced mitochondrial membrane potential, and defective autophagy/mitophagy.
• The m.15927G>A mutation progressively induces mitochondrial dysfunction and developmental defects in RGCs.

Conclusions:

• The m.15927G>A mutation causes progressive mitochondrial dysfunction and developmental defects in retinal ganglion cells.
• This study establishes a valuable cellular model for investigating LHON pathogenesis.
• The findings provide a foundation for developing future therapeutic strategies for LHON.