[Music] hello everyone today we will be discussing the mitochondria let's start with a brief introduction mitochondria are intracellular organelles found in almost all human cells mitochondria are thought to be derived from aerobic bacteria that invaded the proto-eukaryotic cell more than a billion years ago and lived in a symbiotic relationship with it exchanging energy in the form of adenosine triphosphate or atp for residents however this endosymbiotic hypothesis is not universally accepted and has been challenged each human cell contains on average hundreds to thousands of mitochondria the exception is mature red blood cells which rely exclusively on anaerobic metabolism and contain no mitochondria although mitochondria were originally represented as individual isolated organelles it is now recognized that mitochondria form a dynamic connected network also called a reticulum or a syncitium as zygote mitochondria are derived from the ovum their inheritance is maternal now let's look at some mitochondrial compartments mitochondria have four main compartments the outer membrane which is permeable to certain ions and small molecules the inter membrane space which has a composition similar to that of cytosol the inner membrane in which respiratory chain proteins are found by the way the inner membrane is folded into multiple cristae allowing for large surface areas and the matrix or the inner part of the mitochondrion where most of the metabolic reactions take place the mitochondrial dna is found within dna protein complexes called nucleoids in the mitochondrial matrix now let's discuss some functions of the mitochondria mitochondria are intercellular organelles that are essential for aerobic metabolism and energy production through oxidative phosphorylation which is accomplished by the respiratory chain mitochondria are involved in several other metabolic pathways including beta oxidation the krebs cycle and synthesis of iron sulfur clusters in addition mitochondria maintain replicate and transcribe their own dna and translate messenger rna or mrna into protein the import and assembly of proteins is another important mitochondrial function since most proteins that the mitochondria require are encoded by nuclear dna and translated in the cytosol specifically human mitochondrial dna is a double-stranded circular molecule containing approximately 16 500 base pairs compared with over a billion in nuclear dna it codes for 13 protein subunits that are associated with proteins encoded by nuclear genes to form four enzyme complexes plus two ribosomal and 22 transfer rnas that are needed for protein production by the intra-mitochondrial ribosomes the ongoing remodeling of the mitochondrial network is also a function of the mitochondria additional roles of the mitochondria include being active in apoptosis production of reaction oxygen species calcium homeostasis maintenance of the lipid membrane and immunity have been described mitochondria have an ineffective dna repair system and the mutation rate for the mitochondrial dna is over 10 times the rate for nuclear dna here are some mitochondrial markers for the inner membrane the markers are atp synthase and succinate dehydrogenase for the inter membrane space the markers are creatine kinase and adenylyl kinase the matrix markers are glutamate dehydrogenase pyruvate dehydrogenase and enzymes of the tca cycle and oxidation of fatty acids but you may ask how is protein imported into the mitochondria well there are two ways there is tom translocase of the outer membrane and tim translocase of the inner membrane both are import receptors and translocators protein passes through tom and enters inter membrane space then passes through tim to enter the [Music] matrix [Music] do [Music] the tom tim alignment is also an important topic research suggests that the tim tethers to the outer membrane and diffuses laterally until it comes in contact with the tom or the pre-sequence complex protein can enter the matrix in an energy-dependent manner the pre-sequence is cleaved by peptidase and chaperones assist in folding proteins transmembrane domain can diffuse laterally out of tim and embed in inner membranes now you might hear all this and think well where's the clinical link well let's explore that in particular let's look at neurodegenerative disorders these are often caused by defects in translocases genetic disorders in tim production results in deafness and dystonia now let's discuss symbiogenesis the dna and ribosomes of the mitochondria and prokaryotes have many similarities the discovery of this fact resulted in the endosymbiotic theory of mitochondrial evolution which is that mitochondria were originally independent prokaryotic bacteria with the special ability to produce energy through oxidative phosphorylation and were eventually engulfed by eukaryotic cells as a result the prokaryotic cells lost part of their dna and their ability to live independently while the eukaryotic host cell became dependent on the energy produced by the incorporated bacterium let's look at some mitochondrial myopathies mitochondrial myopathies are the group of disorders characterized by an impaired energy production in the form of atp that mainly affects organs with a high energy demand such as the brain these are extremely rare and the prevalence is a ratio of about thirteen to every one hundred thousand one of these myopathies is etiology these are caused by mutations and or defects in the mitochondrial dna which are maternally inherited children of an affected mother will likewise be affected the genetic expression is variable due to heteroplasmy heteroplasmy is the heterogeneity of the mitochondrial dna within a cell it's caused by selective distribution of mitochondria with mutated dna and can result in variable expression of diseases that follow mitochondrial inheritance another myopathy is pathophysiology these are mutations and or defects in the mitochondrial dna that lead to impaired oxidative phosphorylation which therein causes a decreased production of atp which thus creates an increased glycolysis which then causes an excessive production of pyruvate which finally leads to an accumulation of lactate and alanine organs with a high energy requirement such as the retina brain inner ear skeletal cardiac muscles or others are particularly affected some common clinical features include commonly external ophthalmoplegia ptosis and or exertion muscle weakness some diagnostics are genetic studies including mitochondrial dna and muscle biopsy immunohistochemistry typically shows ragged red fibers which are caused by subsarcolemyl and intramyofibrillar accumulation of defective mitochondria in muscles or mitochondria stain red laboratory studies for this include normal ck and elevated lactate and alanine in serum urine and or csf the treatment is mainly supportive now let's discuss some subtypes of mitochondrial myopathies the first is m-e-l-a-s it is characterized by mitochondrial encephalomyopathy lactic acidosis and recurring stroke-like episodes other findings include muscle weakness and tonic clonic seizures the next subtype is m-e-r-r-f this is characterized by myoclinic epilepsy with ragged red fibers we do know the cause there is a point mutation of the hundred 8 forty fourth base pair of mitochondrial dna in approximately eighty percent of cases specifically in the mitochondrial mttk gene this leads to the destruction of important proteins involved in oxidative phosphorylation other findings include generalized seizures cerebellar ataxia and dementia the third and final subtype is cpeo this is characterized by chronic progressive external ophthalmalplegia with bilateral ptosis kern's sayer syndrome is characterized by ophthalmoplegia and retinous pigmentosa impaired electrical activity of the heart especially the av block and l-h-o-n liber hereditary optic neuropathy let's now discuss some of the epidemiology this most commonly occurs in teenagers and young adults with the male to female ratio being about three to one the cause is cellular death in the optic nerve neurons and clinical features are painless acute or sub-acute bilateral vision loss which is usually irreversible there is also lee syndrome the clinical features of lee syndrome include vomiting diarrhea dysphagia failure to thrive hypotonia dystonia ataxia rapidly progressive psychomotor regression ophthalmoparesis nystagmus and optic atrophy death usually occurs within two to three years due to respiratory failure