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 an inherited eye disease caused by mitochondrial DNA (mtDNA) mutations.
• The m.15927G>A mutation in mitochondrial tRNA^Thr (MT-TT) disrupts tRNA function and causes mitochondrial dysfunction.
• Lack of suitable LHON models hinders understanding of disease mechanisms and tissue-specific effects.

Purpose of the Study:

• To establish and characterize a cellular model of LHON using induced pluripotent stem cells (iPSCs).
• To investigate the impact of the m.15927G>A mutation on retinal ganglion cells (RGCs) and their precursors.
• To explore mitochondrial dysfunction and autophagy/mitophagy defects in LHON pathogenesis.

Main Methods:

• Generation of iPSCs from a Chinese family with the m.15927G>A LHON mutation and from a control subject.
• Differentiation of iPSCs into neural progenitor cells (NPCs) and RGC-like cells.
• Assessment of mitochondrial dynamics, function, reactive oxygen species (ROS) production, mitochondrial membrane potential, and autophagy/mitophagy.

Main Results:

• Mutant iPSCs and NPCs showed abnormal mitochondrial dynamics, dysfunction, and impaired autophagy/mitophagy.
• LHON-mutant RGC-like cells exhibited shorter neurites, imbalanced mitochondrial dynamics, elevated ROS, reduced mitochondrial membrane potential, and defective autophagy/mitophagy.
• The m.15927G>A mutation progressively impairs RGC development and mitochondrial function.

Conclusions:

• The study provides a valuable RGC-like cell model for LHON research.
• The m.15927G>A mutation induces progressive mitochondrial dysfunction and developmental defects in RGCs.
• This model offers insights into LHON pathogenesis and aids in developing future therapies.