A new mitochondrial DNA deletion associated with diabetic amyotrophy, diabetic myoatrophy and diabetic fatty liver

Abstract

Mitochondrial dysfunctions of the muscle in diabetic amyotrophy and of the liver in diabetic fatty liver have been reported. We investigated mitochondrial gene mutations in three cases: (1) a patient with diabetic amyotrophy in the muscles of the lower extremities, and neuropathy; (2) 5 diabetics with myoatrophy, diabetic nephropathy, and chronic renal failure; and (3) an IDDM patient with a diabetic fatty liver. We identified a 5778-bp deletion (8214-13991) in mitochondrial DNA from the muscle and liver biopsy specimens by the primer shift PCR and PCR-direct sequence methods. It is speculated that 5778-bp deletion is due to homogeneous recombination in the 7-bp repeat sequence of TCCTAGA flanking the region deleted in the mitochondrial DNA. Determination of respiratory chain enzyme activities in fresh muscle mitochondria demonstrated the defect in complex I activity. The deletion covers areas coding ND3, ND4, ND4L, and ND5 in complex I. The 5778-bp deletion might cause a defect in mitochondrial oxidative phosphorylation and contribute to the pathogenesis of diabetic amyotrophy, myoatrophy with diabetic nephropathy, and chronic renal failure, as well as diabetic fatty liver in IDDM.

Mitochondrial DNA deletion and sarcopenia

“…However, due to the heteroplasmic state of the cells that contain both normal and mutant mitochondria and to the presence of allelic variants, it is often difficult to establish the real impact of these mutations on complex I assembly and activity in patients. In this respect, we observed deletions in the 8577–10407bp and 10233–11249 bp regions associated with significant decrease in complex I activity as has been reported by Henokio et al 41 . They reported 5778-bp deletion (8214–13991) in mitochondrial DNA from the muscle and liver biopsy specimens linked to the defect in complex I activity.…”

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

“…This would have the effect to compromise the functioning of the oxidative phosphorylation system as a result of the loss of mitochondrial gene products that make up segments of the respiratory chain; subsequently leading to more ROS production. This concept is supported by observations of significant mtDNA mutations and abnormalities in NASH patients [67,68] and in an animal model of fatty liver disease [60]. Whether these mtDNA defects translate into decreased activity and content of the respiratory complexes in obesity induced fatty liver disease is not known.…”

Noninsulin-Dependent Diabetes Mellitus as a Mitochondrial Genomic Disease

“…They exhibit hyperglycemia that is due to a significantly reduced insulin secretory capacity that progresses with age (67-74). 3394 3396 3423 3434 3438 3447 3480 3483 421 6 491 7 5780 7476 8245 825 1 8344 10398 11778 12308 14709 15904 15924 15927 15928 16069 16093 161 26 A+G A+G C+T T+C T+C T+C G+A A+G T+C T+C G+T A+G G+A A+G A+G G+A T+C A+G G+A C+T A+G G+A A+G C+T T+C A+G T+C C+T A+G G+A G+A C+T T+C liver, which is not an uncommon feature of diabetes mellitus (73). P-Cell loss is seen (77) as well as defects in glucoseinduced signaling of insulin release (47,77,78).…”