A mitochondrial DNA deletion presenting with corneal clouding and severe Fanconi syndrome

Lee, Joyce J.; Tripi, Laura M.; Erbe, Richard W.; Garimella-Krovi, Sudha; Springate, James E.

doi:10.1007/s00467-011-2096-2

Cited by 15 publications

(7 citation statements)

References 14 publications

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“…Similar reports exist for Kearns-Sayre (KSS) [47][48][49][50] and Leigh syndrome [40]. Several studies have found large mtDNA deletions in mitochondrial DNA to be the underlying cause, ranging from 2.7 to 7.4 kbp deletions [48,[51][52][53][54][55]. Overall, these patients show phenotypic similarities to Pearson and Kearns-Sayre syndromes.…”

Section: Mutationssupporting

confidence: 72%

Mitochondrial DNA mutations in renal disease: an overview

Govers

Toka²,

Hariri

et al. 2020

Pediatr Nephrol

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Kidneys have a high energy demand to facilitate the reabsorption of the glomerular filtrate. For this reason, renal cells have a high density of mitochondria. Mitochondrial cytopathies can be the result of a mutation in both mitochondrial and nuclear DNA. Mitochondrial dysfunction can lead to a variety of renal manifestations. Examples of tubular manifestations are renal Fanconi Syndrome, which is often found in patients diagnosed with Kearns-Sayre and Pearson's marrow-pancreas syndrome, and distal tubulopathies, which result in electrolyte disturbances such as hypomagnesemia. Nephrotic syndrome can be a glomerular manifestation of mitochondrial dysfunction and is typically associated with focal segmental glomerular sclerosis on histology. Tubulointerstitial nephritis can also be seen in mitochondrial cytopathies and may lead to end-stage renal disease. The underlying mechanisms of these cytopathies remain incompletely understood; therefore, current therapies focus mainly on symptom relief. A better understanding of the molecular disease mechanisms is critical in order to improve treatments.

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Section: Mutationssupporting

confidence: 72%

Mitochondrial DNA mutations in renal disease: an overview

Govers

Toka²,

Hariri

et al. 2020

Pediatr Nephrol

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“…The most common tubular defect associated with MCs is Toni-Debré-Fanconi syndrome, a rare disorder characterized by impaired tubular reabsorption. Mutations and large mtDNA deletions have been reported in patients with this syndrome (Lee et al 2012), associated with mitochondrial respiratory complex defects and giant atypical mitochondria (Au et al 2007). Kearns–Sayre syndrome, an MC caused by deletions of mtDNA and characterized by isolated involvement of the muscles controlling eyelid movement, may present with renal involvement resembling Barter syndrome (Emma et al 2006).…”

Section: Evidence Of Mitochondrial Injury In Renal Diseasementioning

confidence: 99%

The Emerging Role of Mitochondrial Targeting in Kidney Disease

Eirin

Lerman

2016

Handbook of Experimental Pharmacology

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Renal disease affects millions of people worldwide, imposing an enormous financial burden for health-care systems. Recent evidence suggests that mitochondria play an important role in the pathogenesis of different forms of renal disease, including genetic defects, acute kidney injury, chronic kidney disease, aging, renal tumors, and transplant nephropathy. Renal mitochondrial abnormalities and dysfunction affect several cellular pathways, leading to increased oxidative stress, apoptosis, microvascular loss, and fibrosis, all of which compromise renal function. Over recent years, compounds that specifically target mitochondria have emerged as promising therapeutic options for patients with renal disease. Although the most compelling evidence is based on preclinical studies, several compounds are currently being tested in clinical trials. This chapter provides an overview of the involvement of mitochondrial dysfunction in renal disease and summarizes the current knowledge on mitochondria-targeted strategies to attenuate renal disease.

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“…[22][23][24] Furthermore, the renal phenotype of HNF1B mutated individuals overlaps with that of patients with renal mitochondrial disorders (i.e., interstitial fibrosis, electrolyte disorders, and rarely, proximal tubular dysfunction). 15,25,26 We therefore hypothesized that (1) HNF-1b may directly control PPARGC1A expression and subsequent mitochondrial biogenesis or function in the postembryonic kidney, thus shifting the paradigm of the HNF1B-related nephropathy in adulthood from a developmental nephropathy to a mitochondrial disorder; and (2) transient HNF-1b inhibition may control the mitochondrial dysfunction observed at the early phases of AKI.…”

mentioning

confidence: 99%

Hepatocyte Nuclear Factor-1β Controls Mitochondrial Respiration in Renal Tubular Cells

Casemayou

Fournel

Bagattin

et al. 2017

JASN

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AKI is a frequent condition that involves renal microcirculation impairment, infiltration of inflammatory cells with local production of proinflammatory cytokines, and subsequent epithelial disorders and mitochondrial dysfunction. Peroxisome proliferator-activated receptor coactivator 1- (PPARGC1A), a coactivator of the transcription factor PPAR- that controls mitochondrial biogenesis and function, has a pivotal role in the early dysfunction of the proximal tubule and the subsequent renal repair. Here, we evaluated the potential role of hepatocyte nuclear factor-1 (HNF-1) in regulating PPARGC1A expression in AKI. In mice, endotoxin injection to induce AKI also induced early and transient inflammation and PPARGC1A inhibition, which overlapped with downregulation of the HNF-1 transcriptional network. , exposure of proximal tubule cells to the inflammatory cytokines IFN- and TNF- led to inhibition of HNF-1 transcriptional activity. Moreover, inhibition of HNF-1 significantly reduced PPARGC1A expression and altered mitochondrial morphology and respiration in proximal tubule cells. Chromatin immunoprecipitation assays and PCR analysis confirmed HNF-1 binding to the promoter in mouse kidneys. We also demonstrated downregulation of renal expression in a patient with an germinal mutation. Thus, we propose that HNF-1 links extracellular inflammatory signals to mitochondrial dysfunction during AKI partly PPARGC1A signaling. Our findings further strengthen the view of-related nephropathy as a mitochondrial disorder in adulthood.

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A mitochondrial DNA deletion presenting with corneal clouding and severe Fanconi syndrome

Cited by 15 publications

References 14 publications

Mitochondrial DNA mutations in renal disease: an overview

Mitochondrial DNA mutations in renal disease: an overview

The Emerging Role of Mitochondrial Targeting in Kidney Disease

Hepatocyte Nuclear Factor-1β Controls Mitochondrial Respiration in Renal Tubular Cells

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