Impaired complex I repair causes recessive Leber’s hereditary optic neuropathy

Abstract

Leber’s hereditary optic neuropathy (LHON) is the most frequent mitochondrial disease and was the first to be genetically defined by a point mutation in mitochondrial DNA (mtDNA). A molecular diagnosis is achieved in up to 95% of cases, the vast majority of which are accounted for by 3 mutations within mitochondrial complex I subunit–encoding genes in the mtDNA (mtLHON). Here, we resolve the enigma of LHON in the absence of pathogenic mtDNA mutations. We describe biallelic mutations in a nuclear encoded gene, DNAJC30 , in 33 unsolved patients from 29 families and establish an autosomal recessive mode of inheritance for LHON (arLHON), which to date has been a prime example of a maternally inherited disorder. Remarkably, all hallmarks of mtLHON were recapitulated, including incomplete penetrance, male predominance, and significant idebenone responsivity. Moreover, by tracking protein turnover in patient-derived cell lines and a DNAJC30 -knockout cellular model, we measured reduced turnover of specific complex I N-module subunits and a resultant impairment of complex I function. These results demonstrate that DNAJC30 is a chaperone protein needed for the efficient exchange of complex I subunits exposed to reactive oxygen species and integral to a mitochondrial complex I repair mechanism, thereby providing the first example to our knowledge of a disease resulting from impaired exchange of assembled respiratory chain subunits.

The Influence of Mitochondrial Dynamics and Function on Retinal Ganglion Cell Susceptibility in Optic Nerve Disease

“…Similarly, families with autosomal recessive LHON (arLHON), which is not maternally transferred, have been found to carry mutations in the nuclear-encoded gene, DNAJC30 . DNAJC30 has been implicated as a chaperone protein that shuttles damaged subunits of Complex I away for turnover [ 183 ]. With these links to Complex I, it is not surprising that the underlying pathology of LHON has been suggested to be tied to inadequate ATP generation and increased ROS production, both due to inefficient electron/proton transport across the MIM.…”

Complexome Profiling: Assembly and Remodeling of Protein Complexes

“…Assembly of protein complexes [70] or even further association of several protein complexes require a coordinated process with the help of chaperons also called assembly factors. In recent years, classical CP became a very popular tool to study the significance of individual subunits and assembly factors of the OXPHOS complexes in bacteria [39,40,61] and mitochondria from mammals [17,21,22,27,28,36,[41][42][43][44][45][46][47][48][49][50]53,[64][65][66] and plants [54][55][56][57]60,62].…”

“…Introducing SILAC as a pulse [74] for several hours followed by CP workflow gives insights into dynamics within protein complexes. This strategy enables the study of remodeling and repair in protein complexes [19,66]. Of mention in that respect is an experiment carried out in differentiated mouse myotubes from C2C12 cells (Figure 2).…”

New avenues for therapy in mitochondrial optic neuropathies

“…DNAJC30 interacts with the mitochondrial ATP synthase machinery and facilitates ATP synthesis as well as acting as a chaperone in exchanging defective complex 1. 14,21 Studies have shown that the gender difference could be attributed to the metabolic regulation of oestrogens that directly or indirectly regulate mitochondrial metabolism. 22,23 Furthermore, recent studies have documented that X-linked nuclear modifiers (PRICKLE3, a mitochondrial protein linked to biogenesis of ATPase) modify the phenotypic manifestation of LHON.…”