Abstract
Here we elucidated the pathogenesis of a 14-year-old Chinese female who initially developed an isolated nephropathy followed by a complex clinical presentation with brain and muscle problems, which indicated that the disease process was possibly due to a mitochondrial dysfunction. Careful evaluation of renal biopsy samples revealed a decreased staining of cells induced by COX and NADH dehydrogenase activities, and a strong fragmentation of the mitochondrial network. These anomalies were due to the presence of a mutation in the mitochondrial ATP6 gene, G8969>A. This mutation leads to replacement of a highly conserved serine residue at position 148 of the a-subunit of ATP synthase. Increasing the mutation load in cybrid cell lines was paralleled by the appearance of abnormal mitochondrial morphologies, diminished respiration and enhanced production of reactive oxygen species. An equivalent of the G8969>A mutation in yeast had dramatic consequences on ATP synthase, with a block in proton translocation. The mutation was particularly abundant (89%) in the kidney compared to blood and urine, which is likely the reason why this organ was affected first. Based on these findings, we suggest that nephrologists should pay more attention to the possibility of a mitochondrial dysfunction when evaluating patients suffering from kidney problems.
Highlights
Mitochondrial dysfunction has been implicated in a broad spectrum of human diseases, often referred to as mitochondrial cytopathies (MCs)
Our study reports the case of a patient initially diagnosed with isolated common immunoglobulin A (IgA) nephropathy followed by brain and muscle problems, a clinical presentation typically observed in mitochondrial cytopathies[2,3,33,34]
We came to suspect a possible involvement of mitochondria in the disease process, which was supported by renal tissues analyses showing an enhanced fragmentation of the mitochondrial network (Fig. 1D) and diminished NADH oxidation and cytochrome c oxidase activities (Fig. 1E), and there was a strong accumulation of lactate in cerebrospinal fluid from the patient (Supplementary Fig. S2)
Summary
Mitochondrial dysfunction has been implicated in a broad spectrum of human diseases, often referred to as mitochondrial cytopathies (MCs). These diseases affect at least 1 in 5,000 live human births[1], and can present either in infancy or adulthood, in a multi-systemic or highly tissue-specific manner. The OXPHOS system has a mixed genetic origin, nuclear and mitochondrial It contains approximately 90 different structural protein subunits of which thirteen are encoded by the mtDNA in humans[5]. We here report a Chinese girl who was admitted to hospital at the age of 14 for a severe IgA nephropathy This is a common glomerulonephritis typically affecting young adults that can occur in children and the elderly. We found that a mutation in the mtDNA that dramatically compromises mitochondrial ATP production contributed to the disease process
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