<P> Damage and subsequent dysfunction in mitochondria is an important factor in a range of human diseases due to their influence in cell metabolism . Mitochondrial disorders often present themselves as neurological disorders, including autism . They can also manifest as myopathy, diabetes, multiple endocrinopathy, and a variety of other systemic disorders . Diseases caused by mutation in the mtDNA include Kearns - Sayre syndrome, MELAS syndrome and Leber's hereditary optic neuropathy . In the vast majority of cases, these diseases are transmitted by a female to her children, as the zygote derives its mitochondria and hence its mtDNA from the ovum . Diseases such as Kearns - Sayre syndrome, Pearson syndrome, and progressive external ophthalmoplegia are thought to be due to large - scale mtDNA rearrangements, whereas other diseases such as MELAS syndrome, Leber's hereditary optic neuropathy, myoclonic epilepsy with ragged red fibers (MERRF), and others are due to point mutations in mtDNA . </P> <P> In other diseases, defects in nuclear genes lead to dysfunction of mitochondrial proteins . This is the case in Friedreich's ataxia, hereditary spastic paraplegia, and Wilson's disease . These diseases are inherited in a dominance relationship, as applies to most other genetic diseases . A variety of disorders can be caused by nuclear mutations of oxidative phosphorylation enzymes, such as coenzyme Q10 deficiency and Barth syndrome . Environmental influences may interact with hereditary predispositions and cause mitochondrial disease . For example, there may be a link between pesticide exposure and the later onset of Parkinson's disease . Other pathologies with etiology involving mitochondrial dysfunction include schizophrenia, bipolar disorder, dementia, Alzheimer's disease, Parkinson's disease, epilepsy, stroke, cardiovascular disease, chronic fatigue syndrome, retinitis pigmentosa, and diabetes mellitus . </P> <P> Mitochondria - mediated oxidative stress plays a role in cardiomyopathy in Type 2 diabetics . Increased fatty acid delivery to the heart increases fatty acid uptake by cardiomyocytes, resulting in increased fatty acid oxidation in these cells . This process increases the reducing equivalents available to the electron transport chain of the mitochondria, ultimately increasing reactive oxygen species (ROS) production . ROS increases uncoupling proteins (UCPs) and potentiate proton leakage through the adenine nucleotide translocator (ANT), the combination of which uncouples the mitochondria . Uncoupling then increases oxygen consumption by the mitochondria, compounding the increase in fatty acid oxidation . This creates a vicious cycle of uncoupling; furthermore, even though oxygen consumption increases, ATP synthesis does not increase proportionally because the mitochondria is uncoupled . Less ATP availability ultimately results in an energy deficit presenting as reduced cardiac efficiency and contractile dysfunction . To compound the problem, impaired sarcoplasmic reticulum calcium release and reduced mitochondrial reuptake limits peak cytosolic levels of the important signaling ion during muscle contraction . The decreased intra-mitochondrial calcium concentration increases dehydrogenase activation and ATP synthesis . So in addition to lower ATP synthesis due to fatty acid oxidation, ATP synthesis is impaired by poor calcium signaling as well, causing cardiac problems for diabetics . </P> <P> Given the role of mitochondria as the cell's powerhouse, there may be some leakage of the high - energy electrons in the respiratory chain to form reactive oxygen species . This was thought to result in significant oxidative stress in the mitochondria with high mutation rates of mitochondrial DNA (mtDNA). Hypothesized links between aging and oxidative stress are not new and were proposed in 1956, which was later refined into the mitochondrial free radical theory of aging . A vicious cycle was thought to occur, as oxidative stress leads to mitochondrial DNA mutations, which can lead to enzymatic abnormalities and further oxidative stress . </P>

Which of these processes takes place in the mitochondria of a cell