TY - JOUR
T1 - Pan-cancer analysis of mitochondria chaperone-client co-expression reveals chaperone functional partitioning
AU - Galai, Geut
AU - Ben-David, Hila
AU - Levin, Liron
AU - Orth, Martin F.
AU - Grünewald, Thomas G.P.
AU - Pilosof, Shai
AU - Berstein, Shimon
AU - Rotblat, Barak
N1 - Funding Information:
Funding: This research was supported by the ISRAEL SCIENCE FOUNDATION (grant No. 1436/19) for BR. The laboratory of T.G.P.G. is supported by the ‘Mehr LEBEN für krebskranke Kinder – Bettina-Bräu-Stiftung’, the Matthias-Lackas Foundation, the Leopold and Carmen Ellinger Foundation, the Barbara & Hubertus Trettner Foundation, the Rolf M. Schwiete Foundation, the Friedrich-Baur Foundation, the German Cancer Aid (DKH-70112257), the Gert und Susanna Mayer Foundation, the Deutsche Forschungsgemeinschaft (DFG-391665916), and the Barbara and Wilfried Mohr Foundation.
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2020/4/1
Y1 - 2020/4/1
N2 - Metabolic reprogramming is a hallmark of cancer. Such reprogramming entails the up-regulation of the expression of specific mitochondrial proteins, thus increasing the burden on the mitochondrial protein quality control. However, very little is known about the specificity of interactions between mitochondrial chaperones and their clients, or to what extent the mitochondrial chaperone–client co-expression is coordinated. We hypothesized that a physical interaction between a chaperone and its client in mitochondria ought to be manifested in the co-expression pattern of both transcripts. Using The Cancer Genome Atlas (TCGA) gene expression data from 13 tumor entities, we constructed the mitochondrial chaperone-client co-expression network. We determined that the network is comprised of three distinct modules, each populated with unique chaperone-clients co-expression pairs belonging to distinct functional groups. Surprisingly, chaperonins HSPD1 and HSPE1, which are known to comprise a functional complex, each occupied a different module: HSPD1 co-expressed with tricarboxylic acid cycle cycle enzymes, while HSPE1 co-expressed with proteins involved in oxidative phosphorylation. Importantly, we found that the genes in each module were enriched for discrete transcription factor binding sites, suggesting the mechanism for the coordinated co-expression. We propose that our mitochondrial chaperone–client interactome can facilitate the identification of chaperones supporting specific mitochondrial pathways and bring forth a fundamental principle in metabolic adaptation.
AB - Metabolic reprogramming is a hallmark of cancer. Such reprogramming entails the up-regulation of the expression of specific mitochondrial proteins, thus increasing the burden on the mitochondrial protein quality control. However, very little is known about the specificity of interactions between mitochondrial chaperones and their clients, or to what extent the mitochondrial chaperone–client co-expression is coordinated. We hypothesized that a physical interaction between a chaperone and its client in mitochondria ought to be manifested in the co-expression pattern of both transcripts. Using The Cancer Genome Atlas (TCGA) gene expression data from 13 tumor entities, we constructed the mitochondrial chaperone-client co-expression network. We determined that the network is comprised of three distinct modules, each populated with unique chaperone-clients co-expression pairs belonging to distinct functional groups. Surprisingly, chaperonins HSPD1 and HSPE1, which are known to comprise a functional complex, each occupied a different module: HSPD1 co-expressed with tricarboxylic acid cycle cycle enzymes, while HSPE1 co-expressed with proteins involved in oxidative phosphorylation. Importantly, we found that the genes in each module were enriched for discrete transcription factor binding sites, suggesting the mechanism for the coordinated co-expression. We propose that our mitochondrial chaperone–client interactome can facilitate the identification of chaperones supporting specific mitochondrial pathways and bring forth a fundamental principle in metabolic adaptation.
KW - Bioinformatics analysis
KW - Cancer
KW - Chaperone
KW - Co-expression
KW - Mitochondria
UR - http://www.scopus.com/inward/record.url?scp=85083048845&partnerID=8YFLogxK
U2 - 10.3390/cancers12040825
DO - 10.3390/cancers12040825
M3 - Article
C2 - 32235444
AN - SCOPUS:85083048845
SN - 2072-6694
VL - 12
JO - Cancers
JF - Cancers
IS - 4
M1 - 825
ER -