The yin and the yang of molecular decompensation in LHON

Abstract

Leber hereditary optic neuropathy (LHON) remains an incompletely understood disease. Reduced penetrance and male prevalence are two active areas of investigation. In fact, the presence of a homoplasmic LHON‐related mtDNA missense mutation, affecting all individuals along a maternal line, is the necessary genetic factor predisposing to develop LHON, but in most individuals it is not sufficient as they remain unaffected lifelong. Other genetic or environmental factor are assumed to play a role. The other point of investigation is the catastrophic nature of disease onset and progression, which defines LHON as a subacute disease.The application of iPSCs technology has advanced our understanding of LHON, refining the understanding of which mechanisms may be crucial to maintain cells compensated or prime them to degeneration. This presentation will focus on the balance between mitochondrial biogenesis and autophagic removal of mitochondria (mitophagy) as the emerging key mechanism priming individuals carrying the LHON mutation to become affected or to remain unaffected, possibly lifelong. This balance can be targeted by therapeutic strategies, opening new avenues to cure LHON.