PMID- 37037306
OWN - NLM
STAT- MEDLINE
DCOM- 20230613
LR  - 20240506
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 299
IP  - 5
DP  - 2023 May
TI  - PTEN-induced kinase PINK1 supports colorectal cancer growth by regulating the 
      labile iron pool.
PG  - 104691
LID - S0021-9258(23)00333-2 [pii]
LID - 10.1016/j.jbc.2023.104691 [doi]
LID - 104691
AB  - Mitophagy is a cargo-specific autophagic process that recycles damaged 
      mitochondria to promote mitochondrial turnover. PTEN-induced putative kinase 1 
      (PINK1) mediates the canonical mitophagic pathway. However, the role of PINK1 in 
      diseases where mitophagy has been purported to play a role, such as colorectal 
      cancer, is unclear. Our results here demonstrate that higher PINK1 expression is 
      positively correlated with decreased colon cancer survival, and mitophagy is 
      required for colon cancer growth. We show that doxycycline-inducible knockdown 
      (KD) of PINK1 in a panel of colon cancer cell lines inhibited proliferation, 
      whereas disruption of other mitophagy receptors did not impact cell growth. We 
      observed that PINK KD led to a decrease in mitochondrial respiration, membrane 
      hyperpolarization, accumulation of mitochondrial DNA, and depletion of 
      antioxidant glutathione. In addition, mitochondria are important hubs for the 
      utilization of iron and synthesizing iron-dependent cofactors such as heme and 
      iron sulfur clusters. We observed an increase in the iron storage protein 
      ferritin and a decreased labile iron pool in the PINK1 KD cells, but total 
      cellular iron or markers of iron starvation/overload were not affected. Finally, 
      cellular iron storage and the labile iron pool are maintained via autophagic 
      degradation of ferritin (ferritinophagy). We found overexpressing nuclear 
      receptor coactivator 4, a key adaptor for ferritinophagy, rescued cell growth and 
      the labile iron pool in PINK1 KD cells. These results indicate that PINK1 
      integrates mitophagy and ferritinophagy to regulate intracellular iron 
      availability and is essential for maintaining intracellular iron homeostasis to 
      support survival and growth in colorectal cancer cells.
CI  - Copyright (c) 2023 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Chen, Brandon
AU  - Chen B
AD  - Department of Molecular and Integrative Physiology, University of Michigan, Ann 
      Arbor, Michigan, USA.
FAU - Das, Nupur K
AU  - Das NK
AD  - Department of Molecular and Integrative Physiology, University of Michigan, Ann 
      Arbor, Michigan, USA.
FAU - Talukder, Indrani
AU  - Talukder I
AD  - Department of Molecular and Integrative Physiology, University of Michigan, Ann 
      Arbor, Michigan, USA.
FAU - Singhal, Rashi
AU  - Singhal R
AD  - Department of Molecular and Integrative Physiology, University of Michigan, Ann 
      Arbor, Michigan, USA.
FAU - Castillo, Cristina
AU  - Castillo C
AD  - Department of Molecular and Integrative Physiology, University of Michigan, Ann 
      Arbor, Michigan, USA.
FAU - Andren, Anthony
AU  - Andren A
AD  - Department of Molecular and Integrative Physiology, University of Michigan, Ann 
      Arbor, Michigan, USA.
FAU - Mancias, Joseph D
AU  - Mancias JD
AD  - Division of Radiation and Genome Stability, Department of Radiation Oncology, 
      Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
FAU - Lyssiotis, Costas A
AU  - Lyssiotis CA
AD  - Department of Molecular and Integrative Physiology, University of Michigan, Ann 
      Arbor, Michigan, USA; University of Michigan Rogel Cancer Center, University of 
      Michigan, Ann Arbor, Michigan, USA; Department of Internal Medicine, University 
      of Michigan, Ann Arbor, Michigan, USA. Electronic address: 
      clyssiot@med.umich.edu.
FAU - Shah, Yatrik M
AU  - Shah YM
AD  - Department of Molecular and Integrative Physiology, University of Michigan, Ann 
      Arbor, Michigan, USA; University of Michigan Rogel Cancer Center, University of 
      Michigan, Ann Arbor, Michigan, USA; Department of Internal Medicine, University 
      of Michigan, Ann Arbor, Michigan, USA. Electronic address: shahy@umich.edu.
LA  - eng
GR  - R01 CA148828/CA/NCI NIH HHS/United States
GR  - R01 DK095201/DK/NIDDK NIH HHS/United States
GR  - T32 GM145470/GM/NIGMS NIH HHS/United States
GR  - P30 DK034933/DK/NIDDK NIH HHS/United States
GR  - R01 CA244931/CA/NCI NIH HHS/United States
GR  - R01 DK124384/DK/NIDDK NIH HHS/United States
GR  - P30 CA046592/CA/NCI NIH HHS/United States
GR  - R01 CA248160/CA/NCI NIH HHS/United States
GR  - R01 CA245546/CA/NCI NIH HHS/United States
GR  - R37 CA237421/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20230408
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 9007-73-2 (Ferritins)
RN  - E1UOL152H7 (Iron)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
RN  - EC 2.7.11.1 (PTEN-induced putative kinase)
SB  - IM
MH  - Humans
MH  - *Colonic Neoplasms/genetics/pathology
MH  - *Colorectal Neoplasms/genetics/pathology
MH  - Ferritins
MH  - Iron/metabolism
MH  - *Protein Kinases/genetics/metabolism
MH  - Ubiquitin-Protein Ligases/metabolism
MH  - *Mitophagy
PMC - PMC10196865
OTO - NOTNLM
OT  - colon cancer
OT  - ferritinophagy
OT  - iron
OT  - mitochondria
OT  - mitophagy
COIS- Conflict of interest C. A. L. has received consulting fees from Astellas 
      Pharmaceuticals, Odyssey Therapeutics, and T-Knife Therapeutics and is an 
      inventor on patents pertaining to Kras-regulated metabolic pathways, redox 
      control pathways in pancreatic cancer, and targeting the GOT1-pathway as a 
      therapeutic approach (US Patent No: 2015126580-A1, 05/07/2015; US Patent No: 
      20190136238, 05/09/2019; International Patent No: WO2013177426-A2, 04/23/2015). 
      J. D. M. reports a patent for the modulation of NCOA4-mediated autophagic 
      targeting of ferritin (PCT/US2015/023142) issued.
EDAT- 2023/04/11 06:00
MHDA- 2023/05/29 06:42
PMCR- 2023/04/08
CRDT- 2023/04/10 19:21
PHST- 2022/10/01 00:00 [received]
PHST- 2023/04/01 00:00 [revised]
PHST- 2023/04/03 00:00 [accepted]
PHST- 2023/05/29 06:42 [medline]
PHST- 2023/04/11 06:00 [pubmed]
PHST- 2023/04/10 19:21 [entrez]
PHST- 2023/04/08 00:00 [pmc-release]
AID - S0021-9258(23)00333-2 [pii]
AID - 104691 [pii]
AID - 10.1016/j.jbc.2023.104691 [doi]
PST - ppublish
SO  - J Biol Chem. 2023 May;299(5):104691. doi: 10.1016/j.jbc.2023.104691. Epub 2023 
      Apr 8.