Efficient mitochondrial biogenesis drives incomplete penetrance in Leber's hereditary optic neuropathy

Carla Giordano, Luisa Iommarini, Luca Giordano, Alessandra Maresca, Annalinda Pisano, Maria Lucia Valentino, Leonardo Caporali, Rocco Liguori, Stefania Deceglie, Marina Roberti, Francesca Fanelli, Flavio Fracasso, Fred N. Ross-Cisneros, Pio D'adamo, Gavin Hudson, Angela Pyle, Patrick Yu-Wai-Man, Patrick F. Chinnery, Massimo Zeviani, Solange R. SalomaoAdriana Berezovsky, Rubens Belfort, Dora Fix Ventura, Milton Moraes, Milton Moraes Filho, Piero Barboni, Federico Sadun, Annamaria De Negri, Alfredo A. Sadun, Andrea Tancredi, Massimiliano Mancini, Giulia D'amati, Paola Loguercio Polosa, Palmiro Cantatore, Valerio Carelli

Research output: Contribution to journalArticlepeer-review


Leber's hereditary optic neuropathy is a maternally inherited blinding disease caused as a result of homoplasmic point mutations in complex I subunit genes of mitochondrial DNA. It is characterized by incomplete penetrance, as only some mutation carriers become affected. Thus, the mitochondrial DNA mutation is necessary but not sufficient to cause optic neuropathy. Environmental triggers and genetic modifying factors have been considered to explain its variable penetrance. We measured the mitochondrial DNA copy number and mitochondrial mass indicators in blood cells from affected and carrier individuals, screening three large pedigrees and 39 independently collected smaller families with Leber's hereditary optic neuropathy, as well as muscle biopsies and cells isolated by laser capturing from post-mortem specimens of retina and optic nerves, the latter being the disease targets. We show that unaffected mutation carriers have a significantly higher mitochondrial DNA copy number and mitochondrial mass compared with their affected relatives and control individuals. Comparative studies of fibroblasts from affected, carriers and controls, under different paradigms of metabolic demand, show that carriers display the highest capacity for activating mitochondrial biogenesis. Therefore we postulate that the increased mitochondrial biogenesis in carriers may overcome some of the pathogenic effect of mitochondrial DNA mutations. Screening of a few selected genetic variants in candidate genes involved in mitochondrial biogenesis failed to reveal any significant association. Our study provides a valuable mechanism to explain variability of penetrance in Leber's hereditary optic neuropathy and clues for high throughput genetic screening to identify the nuclear modifying gene(s), opening an avenue to develop predictive genetic tests on disease risk and therapeutic strategies.

Original languageEnglish
Pages (from-to)335-353
Number of pages19
Issue number2
Publication statusPublished - 2014


  • LHON penetrance
  • mitochondrial biogenesis
  • mtDNA copy number

ASJC Scopus subject areas

  • Clinical Neurology
  • Arts and Humanities (miscellaneous)


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