PMID- 37749555
OWN - NLM
STAT- MEDLINE
DCOM- 20230927
LR  - 20231122
IS  - 1478-811X (Electronic)
IS  - 1478-811X (Linking)
VI  - 21
IP  - 1
DP  - 2023 Sep 25
TI  - Defective quality control autophagy in Hyperhomocysteinemia promotes ER stress 
      and consequent neuronal apoptosis through proteotoxicity.
PG  - 258
LID - 10.1186/s12964-023-01288-w [doi]
LID - 258
AB  - Homocysteine (Hcy), produced physiologically in all cells, is an intermediate 
      metabolite of methionine and cysteine metabolism. Hyperhomocysteinemia (HHcy) 
      resulting from an in-born error of metabolism that leads to accumulation of high 
      levels of Hcy, is associated with vascular damage, neurodegeneration and 
      cognitive decline. Using a HHcy model in neuronal cells, primary cortical neurons 
      and transgenic zebrafish, we demonstrate diminished autophagy and Hcy-induced 
      neurotoxicity associated with mitochondrial dysfunction, fragmentation and 
      apoptosis. We find this mitochondrial dysfunction is due to Hcy-induced 
      proteotoxicity leading to ER stress. We show this sustained proteotoxicity 
      originates from the perturbation of upstream autophagic pathways through an 
      aberrant activation of mTOR and that protetoxic stress act as a feedforward cues 
      to aggravate a sustained ER stress that culminate to mitochondrial apoptosis in 
      HHcy model systems. Using chemical chaperones to mitigate sustained ER stress, 
      Hcy-induced proteotoxicity and consequent neurotoxicity were rescued. We also 
      rescue neuronal lethality by activation of autophagy and thereby reducing 
      proteotoxicity and ER stress. Our findings pave the way to devise new strategies 
      for the treatment of neural and cognitive pathologies reported in HHcy, by either 
      activation of upstream autophagy or by suppression of downstream ER stress. Video 
      Abstract.
CI  - (c) 2023. BioMed Central Ltd., part of Springer Nature.
FAU - Kaur, Bhavneet
AU  - Kaur B
AD  - CSIR-Institute of Genomics & Integrative Biology, Mathura Road, Sukhdev Vihar, 
      New Delhi, 110020, India.
AD  - Academy of Scientific & Innovative Research, Ghaziabad, 201002, India.
FAU - Sharma, Pradeep Kumar
AU  - Sharma PK
AD  - CSIR-Institute of Genomics & Integrative Biology, Mathura Road, Sukhdev Vihar, 
      New Delhi, 110020, India.
AD  - Academy of Scientific & Innovative Research, Ghaziabad, 201002, India.
AD  - CSIR-Indian Institute of Toxicology Research, Lucknow, India.
FAU - Chatterjee, Barun
AU  - Chatterjee B
AD  - CSIR-Institute of Genomics & Integrative Biology, Mathura Road, Sukhdev Vihar, 
      New Delhi, 110020, India.
AD  - Academy of Scientific & Innovative Research, Ghaziabad, 201002, India.
FAU - Bissa, Bhawana
AU  - Bissa B
AD  - CSIR-Institute of Genomics & Integrative Biology, Mathura Road, Sukhdev Vihar, 
      New Delhi, 110020, India.
AD  - Present address: Department of Biochemistry, School of Life Sciences, Central 
      University of Rajasthan, Ajmer, India.
FAU - Nattarayan, Vasugi
AU  - Nattarayan V
AD  - CSIR-Institute of Genomics & Integrative Biology, Mathura Road, Sukhdev Vihar, 
      New Delhi, 110020, India.
FAU - Ramasamy, Soundhar
AU  - Ramasamy S
AD  - CSIR-Institute of Genomics & Integrative Biology, Mathura Road, Sukhdev Vihar, 
      New Delhi, 110020, India.
AD  - Academy of Scientific & Innovative Research, Ghaziabad, 201002, India.
FAU - Bhat, Ajay
AU  - Bhat A
AD  - CSIR-Institute of Genomics & Integrative Biology, Mathura Road, Sukhdev Vihar, 
      New Delhi, 110020, India.
AD  - Academy of Scientific & Innovative Research, Ghaziabad, 201002, India.
FAU - Lal, Megha
AU  - Lal M
AD  - CSIR-Institute of Genomics & Integrative Biology, Mathura Road, Sukhdev Vihar, 
      New Delhi, 110020, India.
AD  - Academy of Scientific & Innovative Research, Ghaziabad, 201002, India.
FAU - Samaddar, Sarbani
AU  - Samaddar S
AD  - National Brain Research Centre, Manesar, India.
FAU - Banerjee, Sourav
AU  - Banerjee S
AD  - National Brain Research Centre, Manesar, India.
FAU - Roy, Soumya Sinha
AU  - Roy SS
AD  - CSIR-Institute of Genomics & Integrative Biology, Mathura Road, Sukhdev Vihar, 
      New Delhi, 110020, India. soumya.roy@igib.res.in.
AD  - Academy of Scientific & Innovative Research, Ghaziabad, 201002, India. 
      soumya.roy@igib.res.in.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Video-Audio Media
DEP - 20230925
PL  - England
TA  - Cell Commun Signal
JT  - Cell communication and signaling : CCS
JID - 101170464
RN  - 0LVT1QZ0BA (Homocysteine)
SB  - IM
MH  - Animals
MH  - *Hyperhomocysteinemia
MH  - Zebrafish
MH  - Apoptosis
MH  - Autophagy
MH  - Homocysteine
MH  - Quality Control
PMC - PMC10518934
OTO - NOTNLM
OT  - Apoptosis
OT  - Autophagy
OT  - CBS
OT  - Endoplasmic reticulum
OT  - Homocysteine
OT  - Hyperhomocysteinemia
OT  - Mitochondria
OT  - Neuron
COIS- The authors declare no competing interests.
EDAT- 2023/09/26 00:42
MHDA- 2023/09/27 06:43
PMCR- 2023/09/25
CRDT- 2023/09/25 23:46
PHST- 2023/03/28 00:00 [received]
PHST- 2023/08/19 00:00 [accepted]
PHST- 2023/09/27 06:43 [medline]
PHST- 2023/09/26 00:42 [pubmed]
PHST- 2023/09/25 23:46 [entrez]
PHST- 2023/09/25 00:00 [pmc-release]
AID - 10.1186/s12964-023-01288-w [pii]
AID - 1288 [pii]
AID - 10.1186/s12964-023-01288-w [doi]
PST - epublish
SO  - Cell Commun Signal. 2023 Sep 25;21(1):258. doi: 10.1186/s12964-023-01288-w.