TY  - CHAP
M1  - Book, Section
TI  - Disorders of the Mitochondrial Carnitine Shuttle
A1  - Stanley, Charles A.
A1  - Palmieri, Ferdinando
A1  - Bennett, Michael J.
A2  - Valle, David L.
A2  - Antonarakis, Stylianos
A2  - Ballabio, Andrea
A2  - Beaudet, Arthur L.
A2  - Mitchell, Grant A.
PY  - 2019
T2  - The Online Metabolic and Molecular Bases of Inherited Disease
AB  - The  carnitine  shuttle  represents  a  mechanism  by  which  long-chain  fatty  acids,  which  are  impermeable  to  the  mitochondrial  membranes,  are  transported  into  the  mitochondrial  matrix  for  the  purpose  β-oxidation  and  energy  production.  The  shuttle  takes  activated  long-chain  fatty  acids  as  their  coenzyme  A  esters,  converts  them  to  the  corresponding  acylcarnitines,  which  are  then  translocated  through  the  inner  mitochondrial  membrane  and  finally  reactivated  to  long-chain  acyl-CoA’s  for  β-oxidation.  The  system  consists  of  three  components:first,carnitine  palmitoyltransferase  1  (CPT1)  at  the  inner  side  of  the  outer  mitochondrial  membrane  converts  acyl-CoAs  to  corresponding  acylcarnitines;next,  carnitine:acylcarnitine  translocase  or  carnitine:acylcarnitine  carrier  (CACT  or  CAC),translocates  acylcarnitines  through  the  inner  mitochondrial  membrane;  finally,carnitine  palmitoyltransferase  2  (CPT2),on  the  innersurface  of  the  inner  mitochondrial  membrane  convertsacylcarnitines  back  to  acyl-CoAs  and  releases  free  carnitinethat  is  recycled  to  the  cytosolby  the  actionof  CACT.CPT1  activity  is  unusual  amongst  the  enzymes  involved  in  fatty  acid  β-oxidation  in  that  tissue-specific  isoforms  exist.  CPT1A  is  found  predominantly  in  liver  and  kidney  (and  of  diagnostic  note,  is  also  expressed  in  skin  fibroblasts);  it  is  highly  allosterically  regulated  byprandial  status.  Post-prandial  intracellular  levels  of  malonyl-CoA  are  high  and  inhibit  CPT1A  activity  thus  switching  off  the  transport  of  fatty  acids  into  the  mitochondria  when  there  is  a  plentiful  supply  of  calories  from  dietary  sources.  During  periods  of  fasting,  intracellular  levels  of  malonyl-CoA  fall  and  relieve  this  inhibition  thus  driving  fatty  acids  into  the  mitochondria  for  the  purpose  of  β-oxidation.  CPT1B  is  found  in  skeletal  and  cardiac  muscle  and  the  kinetics  of  malonyl-CoA  inhibition  are  such  that  these  tissues  can  still  utilize  fatty  acids  during  periods  of  high  demand  and  not  only  during  states  of  prolonged  fasting.CPT1C  is  expressed  predominantly  in  brain  and  its  functions  are  still  being  evaluated.Autosomal  recessively  inherited  genetic  disorders  of  all  three  components  of  the  carnitine  shuttle  have  been  described.  All  three  disorders  present  as  defects  of  long-chain  fatty  acid  oxidation.  So  far  CPT1A  is  the  only  known  defect  affecting  CPT1  activity  (MIM  255120).  CPT1A  deficiency  is  primarily  a  disorder  of  hepatic  fasting  intolerance  and  signs  and  symptoms  are  those  of  failure  to  generate  ketone  bodies  by  the  liver  in  response  to  reduced  caloric  intake.  Patients  may  also  have  renal  tubular  acidosis.  CACT  and  CPT2  enzymes  are  expressed  in  all  tissues  and  signs  and  symptoms  of  CACT  deficiency  (MIM  212138)  and  CPT2  deficiency  (MIM  255110,  600649,  608836  representing  neonatal  lethal,  infantile  and  adult  presentations)  are  systemic  and  include  cardiac  and  skeletal  muscle  involvement  in  addition  to  liver  disease.All  of  the  genes  for  thethree  forms  of  CPT1,  of  CACT  and  of  CPT2  have  been  cloned  in  a  variety  of  species.  In  humans  the  genes  have  been  mapped  as  follows:  CPT1A  1on  11q13.3,  CPT1B  on  22q13.33,  CPT1C  on  19q13.33,  CACT  on  3p21.31  and  CPT2  on  1p32.3.CPT1A  deficiency  classically  presents  as  a  fasting-induced  disorder  with  hepatic  failure  leading  to  encephalopathy,  hypoglycemia  and  hypoketosis.  There  may  be  an  associated  moderate  hyperammonemia  and  high  levels  of  plasma  transaminases.  The  acute  clinical  phenotype  is  identical  to  that  seen  in  medium-chain  acyl-CoA  dehydrogenase  (MCAD)  deficiency  and  similar  to  that  described  as  Reyesyndrome.  There  may  also  be  ...
SN  - 
PB  - McGraw-Hill Education
CY  - New York, NY
Y2  - 2024/04/24
UR  - ommbid.mhmedical.com/content.aspx?aid=1181438671
ER  -