Genetic architecture of heart mitochondrial proteome influencing cardiac hypertrophy
- Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, United States
- Department of Integrative Biology and Physiology, Field Systems Biology, Sciences Sorbonne Université, France
- Biochemistry Department, University of Wisconsin-Madison, United States
- Department of Surgery/Division of Cardiac Surgery, University of Southern California Keck School of Medicine, United States
- Metabolic Systems Biology Laboratory, Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Australia
- Jackson Laboratory, United States
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, United States
- Department of Medicine/Division of Cardiology, University of California, Los Angeles, United States
- Division of Oral Biology and Medicine, UCLA School of Dentistry, United States
- UCLA Institute for Quantitative and Computational Biosciences, United States
- Department of Chemistry, University of California, United States
- Department of Integrative Biology and Physiology, University of California, United States
- Department of Physiology, University of Oklahoma Health Sciences Center, United States
- Center for Epigenetics and Metabolism, United States
- Department of Biological Chemistry, University of California, United States
- Department of Anatomy and Physiology, University of Melbourne, Australia
- Department of Human Genetics, University of California, United States
- Department of Microbiology, Immunology and Molecular Genetics, University of California, United States
Figures
Figure 1
Genetic architecture of heart mitochondrial proteome.
(A) High-resolution association mapping of 848 heart mitochondrial proteins from 72 HMDP strains to identify pQTL networks. Associations between protein abundance levels and genetic variants located …
Figure 2
Chr13 locus controls mitochondrial complex-I via miR-27b/NDUFS4 axis.
(A) Circos plot showing chr13 hotspot. Each line signifies a significant association between the genetic variants and the respective protein levels with candidate genes being highlighted. (B) …
-
Figure 2—source data 1
Uncropped blots for Figure 2, panel J.
Uncropped immunoblots probed for NDUFS4 (left) and ACTIN (right) protein levels in NRVMs transfected with mature miR-27b in the presence or absence of PE treatment. Corresponding molecular weight markers are labelled on the right side of each blot.
- https://cdn.elifesciences.org/articles/82619/elife-82619-fig2-data1-v1.pdf
-
Figure 2—source data 2
Raw unedited and uncropped blots for Figure 2, panel J.
- https://cdn.elifesciences.org/articles/82619/elife-82619-fig2-data2-v1.zip
Figure 3
Chr17 locus controls mitoribosomes via LRPPRC/SLIRP.
(A) Circos plot showing chr17 hotspot. Each line signifies a significant association between the genetic variants and the respective protein levels with candidate genes being highlighted. (B) …
-
Figure 3—source data 1
Raw data for Figure 3, panel H.
Association p values between mtDNA-encoded mRNA expression or protein abundance levels and peak SNP (rs46340181) associated with chr17 locus in both sexes of HMDP. p Values were calculated using FaST-LMM that uses Likelihood-Ratio test.
- https://cdn.elifesciences.org/articles/82619/elife-82619-fig3-data1-v1.xlsx
-
Figure 3—source data 2
Raw data for Figure 3, panel J.
Association p values between mtDNA-encoded complex-I related mRNA expression or protein abundance levels and peak SNP (rs48592660) associated with chr13 locus in both sexes of HMDP. p Values were calculated using FaST-LMM that uses Likelihood-Ratio test.
- https://cdn.elifesciences.org/articles/82619/elife-82619-fig3-data2-v1.xlsx
Figure 4 with 1 supplement
Lrpprc regulates an mt-encoded eQTL hotspot specifically in heart of DO mice.
(A) Heatmap illustrates all eQTL (LOD >6) for mt-encoded transcripts that were identified in Adipose (Wang et al., 2012), Heart (Ruzzenente et al., 2012), Islet (Gu et al., 2016), Liver (Rath et …
Figure 4—figure supplement 1
Mediation analysis identifies Lrpprc as a driver for the heart-specific mt- eQTL hotspot on chr17.
LOD scores for 14 mt-eQTL at ~85 Mbp on chr17 before and after conditioning on Lrpprc cis-eQTL in the heart. The average percent drop in the LOD score for the mt-eQTL upon condition to Lrpprc was …
Figure 5
Chr7 locus affects CoQ metabolism via COQ7.
(A) Circos plot showing chr7 hotspot. Each line signifies a significant association between the genetic variants and the respective protein levels with candidate genes being highlighted. (B) …
Additional files
-
Supplementary file 1
Supplementary tables.
(a) List of HMDP strains used for proteomic analyses and their respective genotypes at the three loci. (b) Five modules of WGCNA and their corresponding proteins. (c) List of proteins associated with chr13 locus listed in Figure 2A. The associated P values between the respective proteins and chr13 locus eigengene pSNP are listed. (d) List of proteins associated with chr17 locus listed in Figure 3A. The associated P values between the respective proteins and chr17 locus eigengene pSNP are listed. (e) List of proteins associated with chr7 locus listed in Figure 4A. The associated P values between the respective proteins and chr7 locus eigengene pSNP are listed. (f) Scoring of miRNA targeting Ndufs4 by nine algorithms and one dataset of experimental validation. (g) List of differentially abundant proteins between the control and Ndufs4-cKO groups, and their P values shown in Figure 2. Only proteins that passed the signifcant cut-off (abs[log2FC]>1 and Padj <0.001) are listed. Proteins overlapping chr13 locus are shown in blue font. (h) List of 157 mt-eQTL (LOD >6) across five tissues in the DO mice as shown in Figure 4A. (i) SNP association profile for mt-Nd5 in heart as shown in Figure 4C. (j) Protein-protein correlations between the three candidates and known hypertrophic markers. The bicor P values between the respective markers and each locus candidate gene are listed.
- https://cdn.elifesciences.org/articles/82619/elife-82619-supp1-v1.xlsx
-
Supplementary file 2
Expression values for mt-encoded transcripts and/or Lrpprc in skeletal muscle (2 a), adipose (2b), islets (2 c), liver (2d) and heart (2e).
- https://cdn.elifesciences.org/articles/82619/elife-82619-supp2-v1.xlsx
-
Transparent reporting form
- https://cdn.elifesciences.org/articles/82619/elife-82619-transrepform1-v1.docx
