Mitochondrial Inheritance

MT-ATP6

20-25% of cases caused by mutation in mtDNA Most common found in THIS = gene encoding a protein in the last complex of the oxidative phosphorylation chain, ATP synthase Without ATP synthase the electric transport chain will not produce any ATP Most common form found as point mutation at nucleotide 8 993 that changes a thymime to a guanine Other genes: MT-ND2, MT-ND3, MT-ND5, MT-ND6

Deafness

Allele 1 555 One in 1/200 people will have likelihood of deafness When exposed to aminoglycoside antibiotics such as gentamicin the likelihood is higher

Leber's hereditary optic neuropathy

Allele 11 778 A number of mtDNA mutations predispose people to THIS Serve visual loss that usually occurs in young adults Visual loss may be more frequent and serve in people who drink alcohol or smoke cigarettes Affects in 1 in 50000 people in Finland

Threshold expression

CAUSES OF DISEASE Mutations in mitochondrial DNA or nuclear genes ACQUIRED MITOCHONDRIAL DYSFUNCTION due to adverse effects of drugs, infections or other environmental causes (occupational chemicals) Division may become clinically apparent once the number of affected mitochondria reaches a certain level or THIS Defects in nuclear encoded mitochondrial genes are associated with anemia, dementia, hypertension, lymphoma, seizures and neurodevelopmental disorders

X-linked leigh disease

Caused by deficiency of the pyruvate dehydrogenase complex subunit encoded by an X-linked disease Affects male children more often than female children (one copy of the X chromosome) Two unaffected parents carrying the mutant allele can have an unaffected and affected child

Heavy strand

DOUBLE STRANDED THIS: guanine-rich 28 genes Light Strand: cytosine-rich 9 genes

Leigh syndrome

Disorder that affects the central nervous system Symptoms will begin in infancy and leading to death within a span of several years However it appears that symptoms can emerge at any age Characterised by the loss of energy production SYMPTOMS: diarrhea, vomiting, seizures and trouble swallowing or sucking As the disease progresses, muscular system is debilitated (brain cannot control contraction) - low muscle tone and strength, involuntary sustained muscle contraction and lack of control over movement Eyes affects: muscles that control eyes Heat and lungs also fail -> respiratory failure most common cause of death Mutations in mtDNA or nuclear encoded genes implicated in disease -latter accounts for majorty

French Canadian Syndrome

Found at much higher rate in the Saguenay-Lac-Saint-Jean region of Quebec Caused by mutation in the LRPPRC gene Located on the small arm of chromosome 2 Both heterozygous and homozygous mutations observed First described in 1993 in 34 children from the region, serve deficiency in COX gene In cells of brain and liver tissue and substantial in fibroblasts and skeletal muscle

Mitochondrial disease

Group of disorders caused by dysfunctional mitochondria Mutation in mitochondrial DNA or mutations in genes of the nuclear DNA Neuromuscular diseases caused by damage to the mitochondria are often called mitochondrial myopathies SYMPTOMS: - poor growth, loss of muscle coordination, muscle weakness - visual problems, hearing problems, learning disabilities - heart disease, liver disease, kidney disease, gastrointestinal disorder, respiratory disorder - neurological problems, dementia DISEASES: - Huntington's disease, Alzheimer's disease, Parkinson's disease, diabetes, bipolar disorder Minor defects cause only "exercise intolerance" with no serious illness or disability Mitochondrial disease worse when the mutations are present in muscle, cerebrum and nerve mitochondria

Nuclear DNA mutations

Inhertied in autosomal recessive pattern Two unaffected parents carrying the mutant allele can have an affected child 70-80% of disease caused by THIS Mutations affect the function or assembly of the fourth complex involved in oxidative phosphorylation, cytochrome C oxidase, cause the most cases of the disease Protein that SURF1 codes for is terminated early and cannot perform its function leading to a deficit of COX protein and therefore reducing the amount of energy

37

Known as mitochondrial DNA (mtDNA) Circular DNA In humans ~ 16,500 base pairs THIS many genes 13 provide enzymes involved in oxidative phosphorylation Remaining genes provide information to make molecules called transfer RNA (tRNA) and ribosomal RNA (rRNA) These genes assemble amino acids into functioning proteins

500

Mitochondrial DNA forms closed circular molecules Each such molecules normally containing a full set of mitochondrial genes Each human mitochondrion contains on average approximately 5 such mtRNA molecules Quantities ranging from 1-15 Each human cell contains about 100 Total number of mtDNA molecules per human cell approximately THIS

Maternally inherited

Mitochondrial DNA is THIS CONTAINS: Origin of replication Control region (d-loop) Cytochrome b NADH dehydrogenase subunits Cytochrome oxidase subunits ATP synthase subunits 16s rRNA 12S rRNA

Chromosomal inheritance

Mitochondrial disease can be inherited maternally and through THIS Way it passes generation to generation varies depending on the disease Mitochondrial genetic mutations in the nuclear DNA can occur in any of the chromosomes Mutations inherited through the chromosomes can be autosomal dominant or recessive AND also sex-linked dominant or recessive THIS follows normal Mendelian laws - BUT the phenotype may be masked Due to complex communication and interaction between mitochondrial and nuclear DNA, even simple inheritance is hard to diagnose Mutations in chromosomal DNA can change the proteins that regulate the production of other proteins in the mitochondria / cytoplasm Slight, if any, noticeable symptoms Other devastating mtRNA mutations are easy to diagnose

Inheritance patterns

Mitochondrial inheritance is non-mendelian (genetic material is not half from each parent) 80% of mitochondrial DNA codes for mitochondrial RNA Most mitochondrial DNA mutations lead to functional problems, manifested as muscle disorders 30 ATP per glucose - in contrast to 2 ATP in glycolysis Slight problems with any one of the numerous enzymes used by the mitochondria can be devastating to the cell and the organism

Mother to offspring

Mitochondrial mutations are passed on 100% of the time from THIS Number of affected mtDNA molecules inherited by a specific offspring can vary greatly: - mitochondria within the fertilised oocyte is what the new life will have to begin with - numbers of affected mitochondria varies from cell to cell - number of mtDHA molecules in the mitochondria varies Even with twins, it is possible for one baby to receive more than half of the mutant DNA molecules, the other twins may only receive a tiny fraction of the mutant mtDNA molecules SOMETIMES mtDNA from sperm cell enters the oocyte but paternal mitochondria are actively decomposed

HIV/AIDS

THIS and the mitochondrial DNA THESE patients are treated with azidothyramidine During the late 1980s it transformed the lives of THESE patients 30% of patients taking AZT were developing complication - Researcher implicated mitochondrial toxicity ACT designed to inhibit an enzyme (DNA polymerase) involved in HIV replication - in this case, mitochondrial DNA polymerase gamma also tageted = abnormal mitochondrial and cell function