Mitochondrial DNA mutations in renal disease: an overview

Abstract

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.

Distinct Mitochondrial Pathologies Caused by Mutations of the Proximal Tubular Enzymes EHHADH and GATM

“…The functional consequences of heteroplasmy depend on the degree of accumulation of the mutated mtDNA, the nature of the mutation, and the particular sensitivity of the affected cells for the mutational consequences. However, renal diseases caused by mutations of mitochondrial DNA were not the focus of this review and interested readers are referred to a recent review ( Govers et al, 2021 ).…”

Mitochondrial Disease and the Kidney With a Special Focus on CoQ10 Deficiency

“…[23][24][25][26][27] Excellent overviews of mitochondrial and nuclear gene mutations causing tubular defects are provided in various reviews. 8,20,[72][73][74] The most reported problem is a proximal tubular defect as proximal tubular cells are relatively J o u r n a l P r e -p r o o f vulnerable to oxidative stress. Most patients present with partial defects, including renal tubular acidosis (RTA), aminoaciduria, glycosuria, hypermagnesuria, or a combination of the above.…”

“… 10 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 Excellent overviews of mitochondrial and nuclear gene mutations causing tubular defects are provided in various reviews. 8 , 20 , 72 , 73 , 74 The most commonly reported problem is a proximal tubular defect, as proximal tubular cells are relatively vulnerable to oxidative stress. Most patients present with partial defects, including renal tubular acidosis (RTA), aminoaciduria, glycosuria, hypermagnesuria, or a combination of the above.…”

Excessively Enlarged Mitochondria in the Kidneys of Diabetic Nephropathy

“…Proximal tubular cells in renal tissue are rich in mitochondria and rely on oxidative phosphorylation for ATP generation [5]. Moreover, the importance of mitochondrial function in the kidneys is evident in inherited mitochondrial diseases with renal impairment [6]. Previously, it has been reported that the mitochondrial membrane potential in endothelial cells and podocytes of the kidneys is reduced by treating high-glucose in DN [7].…”