Pyruvate dehydrogenase complex is a complicated enzyme with multiple components and regulators. Pyruvate dehydrogenase (E1) is a component of PDC, and its subunit E1? is encoded by PDHA1, locating on the X chromosome. Second, mitochondria have a separate set of genes that are different than those found in cell nucleus. Moreover, proteins present in a mitochondrion can be encoded by both mitochondrial located genes and nucleus located genes. Abnormalities of mitochondria in skeletal muscle are found in about 50% of individuals with Leigh syndrome. Complex I (NADH dehydrogenase) deficiency, complex II (succinate dehydrogenase, which is not shown in the video) deficiency, complex III (cytochrome bc1 complex), complex IV (cytochrome oxidase) deficiency, and complex V (ATP synthase) deficiency can all contribute to Leigh syndrome.
Complex I passes electrons from NADH to ubiquinone while pumping hydrogen ions out of the mitochondrial matrix into the space between the two membranes.
Complex II is involved in the Krebs cycle, converting succinate to fumerate and passing electrons to the ubiquinone in the respiratory chain.
Complex III transfers electrons from succinate and nicotinamide adenine dinucleotide-linked dehydrogenases to cytochrome c. The most common cause of Leigh syndrome is mutations in complex IV (also called cytochrome c oxidase or COX). The gene most frequently mutated in COX-deficient Leigh syndrome is SURF1, which is found in nuclear DNA and contributes to the assembly of the COX complex. The French Canadian type of Leigh Syndrome (LSFC) is associated with COX deficiency, which is particularly severe in the liver [6].  LRPPRC gene variation(s) underlies LSFC, and LSFC is inherited in an autosomal recessive mode.


Mutations in genes encoding mitochondrial tRNA proteins were found in a few patients and associated with myoclonus epilepsy and ragged red fibers (MERRF) [1].
Breathing problem is common in individuals with Leigh syndrome (LS) and a major cause of mortality. In a mouse model, Surf1 gene (a main cause of COX deficiency) is disrupted and loses its function. Frequent causes include deficiency of pyruvate dehydrogenase complex and respiratory chain complexes of mitochondria. Mutations in PDHA1 are most often associated with PDC deficiency, and the corresponding Leigh syndrome shows an X-linked inheritance pattern. The abnormalities are diverse, and many different components in mitochondria can be affected [3].
All four subunits of complex II are encoded by nuclear DNA, and the Leigh syndrome with Complex II deficiency has an autosomal recessive inheritance [4].
In cellular respiration, the COX complex provides energy for the next step that would generate ATP.
ATP synthase) is encoded by mitochondrial DNA and its defects can contribute to Leigh syndrome.  Consequently, the related Leigh syndrome shows a maternal mode of inheritance. These mice have a higher frequency of breathing and abnormal responses to low oxygen level, suggesting the need to develop therapeutic strategies to protect patients with COX deficiency from low oxygen content [7]. Hypoxic and hypercapnic challenges unveil respiratory vulnerability of Surf1 knockout mice, an animal model of Leigh syndrome . The gene mutations related to Leigh syndrome affect proteins in complex I, II, IV or V, or can disturb the assembly of these complexes [3].


Consequently, Leigh Syndrome with mutations in the nuclear-encoded subunits shows an autosomal recessive inheritance pattern while Leigh syndrome with mutations in the mitochondrial-encoded subunits shows a maternal inheritance pattern [4]. It is encoded by BCS1L gene on chromosome 2, and the associated Leigh syndrome is relatively rare [1] [5]. Mutations in the SURF1 gene lead to the production of abnormal SURF1 proteins that would reduce the formation of COX complexes, thus impairing mitochondrial ATP production [3]. The most common mutation is on the 8993th amino acid, a change from threonine to glycine [4]. Consequently, fewer ATPs can be produced and pyruvates are shunted to lactate production pathway, increasing lactate level.
Five protein complexes (complex I, complex II, complex III, complex IV and complex V) are involved in the process of oxidative phosphorylation, which eventually produce ATP.
Therefore, the activities of these complexes are disrupted or reduced, ultimately leading to Leigh syndrome. Although autosomal recessive inheritance is more common for COX deficiency, no mutation has been found in the 10 nuclear-encoded subunits.  In fact, the underlying genetic defects are unknown in the majority of the patients [4].
Attempting to aggressively control blood sugar with insulin and sulfonylurea drugs could lead to over-treatment and hypoglycemia (low blood sugar), Yale researchers report.Diabetes overtreatment may threaten the health and lives of older patients.
We have been potentially over-treating a substantial proportion of the population.” This study asks some very valid questions and shows that even though managing diabetes is very important, we need to find a way to tailor treatments for individual patients and needs.



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