The mechanism of action of a mutant mitochondrial fission protein

• Main Author: Leo, Vincenzo Carlo
• Other Authors: Dear, N.
• Published: University of Leeds 2013
• Subjects: 612.1
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.589335

Cardiovascular disease is the most common cause of morbidity and mortality worldwide, of which cardiomyopathies account for a proportion. One of the hallmarks of progressive heart disease is diminished energy metabolism associated with cardiac mitochondrial dysfunction. Recent evidence directly implicates malfunctioning mitochondria and altered mitochondrial dynamics in the development of heart disease. Yet, little is known about mitochondrial remodelling changes that might contribute to the development of heart failure. A recently identified mouse mutant in the Dnm1l gene, Python, leads to the development of dilated cardiomyopathy at specific ages. The work reported herein focussed on understanding the mechanisms responsible for the development of cardiomyopathy in this model. Evidence was obtained of alteration in mitochondria, peroxisome and endoplasmic reticulum (ER) morphology in various cell types. There was a suggestion of altered physical interaction between the mitochondria and the ER. Increased cytosolic calcium levels and reduced mitochondrial uptake of calcium were also observed in Python fibroblasts. Mitochondrial membranes were also depolarised. These changes resulted in reduced oxidative phosphorylation activity in the hearts of Python mice, which showed a progressive reduction with age. Ultimately a decrease in ATP levels occurred, which was unsustainable with normal heart function. DNM1L expression was found to increase with age in hearts of wild type mice, but not other tissues. This may be suggestive of an increase in the importance for the DNM1L protein in the ageing heart, though the exact reasons for this remain elusive. Fragmented mitochondria have been postulated to contribute to the development of Huntington’s disease. However, a reduction in fragmentation through introduction of the Python mutation did not alleviate the progressive development of symptoms in these animals. We hypothesize that the Python mutation impairs the ability of mitochondrial-ER tethering. Subsequent dysfunctional mitochondrial calcium uptake and altered mitochondrial membrane potential, leads to a progressive decline in oxidative phosphorylation activity and ATP production.