PMID- 37858707
OWN - NLM
STAT- MEDLINE
DCOM- 20231129
LR  - 20231208
IS  - 1089-8638 (Electronic)
IS  - 0022-2836 (Linking)
VI  - 435
IP  - 23
DP  - 2023 Dec 1
TI  - FDX1 Is Required for the Biogenesis of Mitochondrial Cytochrome c Oxidase in 
      Mammalian Cells.
PG  - 168317
LID - S0022-2836(23)00428-X [pii]
LID - 10.1016/j.jmb.2023.168317 [doi]
AB  - Ferredoxins (FDXs) are evolutionarily conserved iron-sulfur (Fe-S) proteins that 
      function as electron transfer proteins in diverse metabolic pathways. Mammalian 
      mitochondria contain two ferredoxins, FDX1 and FDX2, which share a high degree of 
      structural similarity but exhibit different functionalities. Previous studies 
      have established the unique role of FDX2 in the biogenesis of Fe-S clusters; 
      however, FDX1 seems to have multiple targets in vivo, some of which are only 
      recently emerging. Using CRISPR-Cas9-based loss-of-function studies in rat 
      cardiomyocyte cell line, we demonstrate an essential requirement of FDX1 in 
      mitochondrial respiration and energy production. We attribute reduced 
      mitochondrial respiration to a specific decrease in the abundance and assembly of 
      cytochrome c oxidase (CcO), a mitochondrial heme-copper oxidase and the terminal 
      enzyme of the mitochondrial respiratory chain. FDX1 knockout cells have reduced 
      levels of copper and heme a/a(3), factors that are essential for the maturation 
      of the CcO enzyme complex. Copper supplementation failed to rescue CcO 
      biogenesis, but overexpression of heme a synthase, COX15, partially rescued COX1 
      abundance in FDX1 knockout cells. This finding links FDX1 function to heme a 
      biosynthesis, and places it upstream of COX15 in CcO biogenesis like its 
      ancestral yeast homolog. Taken together, our work has identified FDX1 as a 
      critical CcO biogenesis factor in mammalian cells.
CI  - Copyright (c) 2023 Elsevier Ltd. All rights reserved.
FAU - Zulkifli, Mohammad
AU  - Zulkifli M
AD  - Department of Biochemistry and Biophysics, MS 3474, Texas A&M University, College 
      Station, TX 77843, USA. Electronic address: mohammad.zulkifli@ag.tamu.edu.
FAU - Okonkwo, Adriana U
AU  - Okonkwo AU
AD  - Department of Biochemistry and Biophysics, MS 3474, Texas A&M University, College 
      Station, TX 77843, USA.
FAU - Gohil, Vishal M
AU  - Gohil VM
AD  - Department of Biochemistry and Biophysics, MS 3474, Texas A&M University, College 
      Station, TX 77843, USA. Electronic address: vgohil@tamu.edu.
LA  - eng
GR  - R01 GM143630/GM/NIGMS NIH HHS/United States
GR  - R01 GM111672/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20231017
PL  - Netherlands
TA  - J Mol Biol
JT  - Journal of molecular biology
JID - 2985088R
RN  - EC 1.9.3.1 (Electron Transport Complex IV)
RN  - 0 (Ferredoxins)
RN  - 0 (Mitochondrial Proteins)
RN  - 789U1901C5 (Copper)
SB  - IM
MH  - Animals
MH  - *Electron Transport Complex IV/biosynthesis/genetics
MH  - *Ferredoxins/genetics/metabolism
MH  - Mitochondria/metabolism
MH  - Mitochondrial Proteins/genetics/metabolism
MH  - Rats
MH  - Cell Line
MH  - Myocytes, Cardiac
MH  - Copper/metabolism
OTO - NOTNLM
OT  - COX1
OT  - copper
OT  - heme a
OT  - mitochondria
OT  - respiration
COIS- Declaration of competing interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2023/10/20 06:42
MHDA- 2023/11/13 06:42
CRDT- 2023/10/20 00:32
PHST- 2023/07/23 00:00 [received]
PHST- 2023/10/10 00:00 [revised]
PHST- 2023/10/12 00:00 [accepted]
PHST- 2023/11/13 06:42 [medline]
PHST- 2023/10/20 06:42 [pubmed]
PHST- 2023/10/20 00:32 [entrez]
AID - S0022-2836(23)00428-X [pii]
AID - 10.1016/j.jmb.2023.168317 [doi]
PST - ppublish
SO  - J Mol Biol. 2023 Dec 1;435(23):168317. doi: 10.1016/j.jmb.2023.168317. Epub 2023 
      Oct 17.