The urinary proteome and metabonome differ from normal in adults with mitochondrial disease

Abstract

We studied the extent and nature of renal involvement in a cohort of 117 adult patients with mitochondrial disease, by measuring urinary retinol-binding protein (RBP) and albumin; established markers of tubular and glomerular dysfunction, respectively. Seventy-five patients had the m.3243A>G mutation and the most frequent phenotypes within the entire cohort were 14 with MELAS, 33 with MIDD, and 17 with MERRF. Urinary RBP was increased in 29 of 75 of m.3243A>G patients, whereas albumin was increased in 23 of the 75. The corresponding numbers were 16 and 14, respectively, in the 42 non-m.3243A>G patients. RBP and albumin were higher in diabetic m.3243A>G patients than in nondiabetics, but there were no significant differences across the three major clinical phenotypes. The urine proteome (mass spectrometry) and metabonome (nuclear magnetic resonance) in a subset of the m.3243A>G patients were markedly different from controls, with the most significant alterations occurring in lysosomal proteins, calcium-binding proteins, and antioxidant defenses. Differences were also found between asymptomatic m.3243A>G carriers and controls. No patients had an elevated serum creatinine level, but 14% had hyponatremia, 10% had hypophosphatemia, and 14% had hypomagnesemia. Thus, abnormalities in kidney function are common in adults with mitochondrial disease, exist in the absence of elevated serum creatinine, and are not solely explained by diabetes.

Mitochondrial dysfunction in inherited renal disease and acute kidney injury

“…A large-scale proteomic analysis of urine samples from adult patients with mitochondrial diseases showed that 75 of 117 participants carried the mtDNA 3243 A>G mutation 97 . Nearly half of the patients with this mutation had albuminuria and/or low-molecular-weight proteinuria, indicating that mtDNA 3243 A>G probably represents the most common mitochondrial disorder with renal involvement.…”

“…Nearly half of the patients with this mutation had albuminuria and/or low-molecular-weight proteinuria, indicating that mtDNA 3243 A>G probably represents the most common mitochondrial disorder with renal involvement. Approximately half of the patients with this disorder presented with MIDD, whereas most of the remaining patients presented with MELAS or MERRF syndromes 97 .…”

Maternal Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-Like Episodes Syndrome and Neonatal Magnesium Toxicity: A Case Report

“…It is well known that the neonatal kidney function is impaired compared with adults due to immature glomerular filtration and tubular function and reduced kidney perfusion pressure [16]. Moreover, mitochondrial diseases are associated with renal functional impairment, despite normal serum creatinine levels [17]. Magnesium sulfate is exclusively excreted from the body by the kidneys through free glomerular filtration [10].…”

Adult onset tubulo‐interstitial nephropathy in MT‐ND5‐related phenotypes

“…Kidney pathology is more frequently reported in children than in adult . The most common mitochondrial DNA (mtDNA) defects reported with a kidney phenotype during adulthood are the mutation m.3243A>G in the tRNA ‐leu gene associated to myopathy encephalopathy lactic acidosis and stroke (MELAS) syndrome and mtDNA large scale deletions associated to Kearns‐Sayre Syndrome . Rare single case reports have described supplemental point mutations, most of them involving tRNA genes .…”

“…The most common mitochondrial DNA (mtDNA) defects reported with a kidney phenotype during adulthood are the mutation m.3243A>G in the tRNA ‐leu gene associated to myopathy encephalopathy lactic acidosis and stroke (MELAS) syndrome and mtDNA large scale deletions associated to Kearns‐Sayre Syndrome . Rare single case reports have described supplemental point mutations, most of them involving tRNA genes . Complex I is the most frequent mitochondrial respiratory chain complex involved in mitochondrial diseases and is associated with a wide range of clinical presentations in children and young adults .…”