RT Book, Section
A1 Shoffner, John M.
A2 Valle, David L.
A2 Antonarakis, Stylianos
A2 Ballabio, Andrea
A2 Beaudet, Arthur L.
A2 Mitchell, Grant A.
SR Print(0)
ID 1181439523
T1 Oxidative Phosphorylation Diseases
T2 The Online Metabolic and Molecular Bases of Inherited Disease
YR 2019
FD 2019
PB McGraw-Hill Education
PP New York, NY
SN 9780071459969
LK ommbid.mhmedical.com/content.aspx?aid=1181439523
RD 2024/04/17
AB Oxidative  phosphorylation  (OXPHOS)  is  composed  of  five  intramitochondrial  enzyme  complexes  (complexes  I  to  V)  that  are  responsible  for  producing  the  majority  of  the  ATP  required  for  normal  cellular  function.  Assembly  and  maintenance  of  OXPHOS  requires  the  coordinate  regulation  of  nuclear  DNA  and  mitochondrial  DNA  (mtDNA)  genes.  The  mtDNA  encodes  12  OXPHOS  subunits,  22  tRNAs,  and  2  rRNAs,  which  provide  the  core  elements  for  OXPHOS  function  and  mitochondrial  protein  synthesis.  The  nuclear  DNA  is  responsible  for  synthesizing  approximately  70  OXPHOS  subunits,  transporting  them  to  the  mitochondria  via  chaperone  proteins,  ensuring  their  passage  across  the  mitochondrial  inner  membrane,  and  coordinating  their  proper  processing  and  assembly.  OXPHOS  is  regulated  by  a  wide  variety  of  factors  and  processes  that  include  hormone  levels,  oxygen  supply,  ion  gradients,  membrane  transporters  such  as  the  adenine  nucleotide  translocase  that  supplies  ADP  for  conversion  to  ATP,  transcription  factors  that  alter  the  levels  of  nuclear  gene  transcription,  tissue-specific  isoforms,  developmental-specific  isoforms,  mitochondrial  replication,  mitochondrial  transcription,  and  mitochondrial  translation.  Defects  in  any  of  these  processes  may  produce  an  OXPHOS  disease.The  cytoplasmic  location  of  the  mtDNA  creates  a  unique  genetics.  Mitochondrial  genetics  is  defined  by  these  principles:  maternal  inheritance,  replicative  segregation,  threshold  expression,  a  high  mtDNA  mutation  rate,  and  a  propensity  to  accumulate  somatic  mutations  with  age.  The  age-related  accumulation  of  mtDNA  mutations  may  contribute  to  the  decline  of  cellular  OXPHOS  function  with  age  and  to  the  progression  of  a  variety  of  degenerative  diseases.  Increases  in  somatic  mtDNA  mutations  are  associated  with  increased  generation  of  free  radicals  that  permanently  damage  the  mtDNA.  The  paucity  of  mtDNA  repair  mechanisms  means  that  once  mtDNA  damage  occurs,  the  mutated  mtDNA  can  persist  in  the  cell  and  clonally  proliferate  over  time.  After  sufficient  levels  of  mutant  mtDNA  are  reached,  OXPHOS  function  begins  to  decline.mtDNA  mutations  are  classified  as  deletions,  duplications,  or  point  mutations.  These  mutations  produce  defective  OXPHOS  subunits  or  abnormalities  in  mitochondrial  protein  synthesis.  Mutations  in  nuclear  OXPHOS  genes  are  the  most  important  causes  for  OXPHOS  diseases.  These  mutations  have  diverse  effects  that  include  increases  in  the  mtDNA  mutation  rate,  decreases  in  the  mtDNA  copy  number,  impaired  OXPHOS  enzyme  assembly,  and  abnormal  function  of  an  OXPHOS  enzyme  subunit.OXPHOS  diseases  are  a  complex  family  of  disorders  with  a  vast  array  of  clinical  manifestations  that  can  be  caused  by  mutations  in  the  nuclear  DNA  or  the  mtDNA.  OXPHOS  mutations  produce  diseases  that  can  affect  a  variety  of  developmental  stages,  tissues,  or  systems,  resulting  in  a  diversity  of  clinical  phenotypes  encountered  in  virtually  all  age  groups.  Hence,  OXPHOS  diseases  should  be  considered  in  the  differential  diagnosis  of  many  familial  diseases.  The  evaluation  of  patients  for  OXPHOS  diseases  is  complex  and  should  be  performed  at  centers  that  are  experienced  with  the  clinical,  biochemical,  and  genetic  characteristics  of  these  disorders.  The  principles  of  mitochondrial  genetics,  as  well  as  of  Mendelian  genetics,  must  be  considered  when  interpreting  the  results  of  this  analysis.  This  approach  permits  developing  an  appropriate  management  plan,  addressing  genetic  counseling  issues  for  the  family,  focusing  on  anxieties  associated  with  the  complexities  of  these  diseases  processes,  providing  patient  education,  and  minimizing  ...