Mitochondrial-nuclear cross-talk in the human brain is modulated by cell type and perturbed in neurodegenerative disease

Aine Fairbrother-Browne; Aminah Ali; Regina Reynolds; Sonia Garcia-Ruiz; David Zhang; Zhongbo Chen; Mina Ryten; Alan Hodgkinson

doi:https://doi.org/10.1038/s42003-021-02792-w

Mitochondrial-nuclear cross-talk in the human brain is modulated by cell type and perturbed in neurodegenerative disease

Aine Fairbrother-Browne, Aminah Ali, Regina Reynolds, Sonia Garcia-Ruiz, David Zhang, Zhongbo Chen, Mina Ryten, Alan Hodgkinson^*

^*Corresponding author for this work

Medical & Molecular Genetics

Research output: Contribution to journal › Article › peer-review

8 Citations (Scopus)

Abstract

Mitochondrial dysfunction contributes to the pathogenesis of many neurodegenerative diseases. The mitochondrial genome encodes core respiratory chain proteins, but the vast majority of mitochondrial proteins are nuclear-encoded, making interactions between the two genomes vital for cell function. Here, we examine these relationships by comparing mitochondrial and nuclear gene expression across different regions of the human brain in healthy and disease cohorts. We find strong regional patterns that are modulated by cell-type and reflect functional specialisation. Nuclear genes causally implicated in sporadic Parkinson’s and Alzheimer’s disease (AD) show much stronger relationships with the mitochondrial genome than expected by chance, and mitochondrial-nuclear relationships are highly perturbed in AD cases, particularly through synaptic and lysosomal pathways, potentially implicating the regulation of energy balance and removal of dysfunction mitochondria in the etiology or progression of the disease. Finally, we present MitoNuclearCOEXPlorer, a tool to interrogate key mitochondria-nuclear relationships in multi-dimensional brain data.

Original language	English
Article number	1262
Journal	Communications Biology
Volume	4
Issue number	1
DOIs	https://doi.org/10.1038/s42003-021-02792-w
Publication status	Published - Dec 2021

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Cite this

@article{ceafb9226368483f98dbd8f8e4025ca2,

title = "Mitochondrial-nuclear cross-talk in the human brain is modulated by cell type and perturbed in neurodegenerative disease",

abstract = "Mitochondrial dysfunction contributes to the pathogenesis of many neurodegenerative diseases. The mitochondrial genome encodes core respiratory chain proteins, but the vast majority of mitochondrial proteins are nuclear-encoded, making interactions between the two genomes vital for cell function. Here, we examine these relationships by comparing mitochondrial and nuclear gene expression across different regions of the human brain in healthy and disease cohorts. We find strong regional patterns that are modulated by cell-type and reflect functional specialisation. Nuclear genes causally implicated in sporadic Parkinson{\textquoteright}s and Alzheimer{\textquoteright}s disease (AD) show much stronger relationships with the mitochondrial genome than expected by chance, and mitochondrial-nuclear relationships are highly perturbed in AD cases, particularly through synaptic and lysosomal pathways, potentially implicating the regulation of energy balance and removal of dysfunction mitochondria in the etiology or progression of the disease. Finally, we present MitoNuclearCOEXPlorer, a tool to interrogate key mitochondria-nuclear relationships in multi-dimensional brain data.",

author = "Aine Fairbrother-Browne and Aminah Ali and Regina Reynolds and Sonia Garcia-Ruiz and David Zhang and Zhongbo Chen and Mina Ryten and Alan Hodgkinson",

note = "Funding Information: A.F.-B. was supported through the award of a Biotechnology and Biological Sciences Research Council (BBSRC UK) London Interdisciplinary Doctoral Fellowship. A.T.A. was supported by the Generation Trust. R.H.R. and Z.C. were supported through the award of Leonard Wolfson Doctoral Training Fellowships in Neurodegeneration. M.R. was supported through the award of a Tenure Track Clinician Scientist Fellowship (MR/ N008324/1). This award also supported D.Z. and S.G.-R. A.H. holds a Medical Research Council (MRC) eMedLab Medical Bioinformatics Career Development Fellowship, funded from award MR/L016311/1. For GTEx data: The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health (commonfund.nih.gov/GTEx). Additional funds were provided by the NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. Donors were enrolled at Biospecimen Source Sites funded by NCI\Leidos Biomedical Research, Inc. subcontracts to the National Disease Research Interchange (10XS170), Roswell Park Cancer Institute (10XS171), and Science Care, Inc. (X10S172). The Laboratory, Data Analysis, and Coordinating Center (LDACC) was funded through a contract (HHSN268201000029C) to the The Broad Institute, Inc. Biorepository operations were funded through a Leidos Biomedical Research, Inc. subcontract to Van Andel Research Institute (10ST1035). Additional data repository and project management were provided by Leidos Biomedical Research, Inc.(HHSN261200800001E). The Brain Bank was supported by University of Miami grant DA006227. Statistical Methods development grants were made to the University of Geneva (MH090941 and MH101814), the University of Chicago (MH090951, MH090937, MH101825, & MH101820), the University of North Carolina—Chapel Hill (MH090936), North Carolina State University (MH101819), Harvard University (MH090948), Stanford University (MH101782), Washington University (MH101810), and to the University of Pennsylvania (MH101822). Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

doi = "https://doi.org/10.1038/s42003-021-02792-w",

language = "English",

volume = "4",

journal = "Communications Biology",

issn = "2399-3642",

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T1 - Mitochondrial-nuclear cross-talk in the human brain is modulated by cell type and perturbed in neurodegenerative disease

AU - Fairbrother-Browne, Aine

AU - Ali, Aminah

AU - Reynolds, Regina

AU - Garcia-Ruiz, Sonia

AU - Zhang, David

AU - Chen, Zhongbo

AU - Ryten, Mina

AU - Hodgkinson, Alan

N1 - Funding Information: A.F.-B. was supported through the award of a Biotechnology and Biological Sciences Research Council (BBSRC UK) London Interdisciplinary Doctoral Fellowship. A.T.A. was supported by the Generation Trust. R.H.R. and Z.C. were supported through the award of Leonard Wolfson Doctoral Training Fellowships in Neurodegeneration. M.R. was supported through the award of a Tenure Track Clinician Scientist Fellowship (MR/ N008324/1). This award also supported D.Z. and S.G.-R. A.H. holds a Medical Research Council (MRC) eMedLab Medical Bioinformatics Career Development Fellowship, funded from award MR/L016311/1. For GTEx data: The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health (commonfund.nih.gov/GTEx). Additional funds were provided by the NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. Donors were enrolled at Biospecimen Source Sites funded by NCI\Leidos Biomedical Research, Inc. subcontracts to the National Disease Research Interchange (10XS170), Roswell Park Cancer Institute (10XS171), and Science Care, Inc. (X10S172). The Laboratory, Data Analysis, and Coordinating Center (LDACC) was funded through a contract (HHSN268201000029C) to the The Broad Institute, Inc. Biorepository operations were funded through a Leidos Biomedical Research, Inc. subcontract to Van Andel Research Institute (10ST1035). Additional data repository and project management were provided by Leidos Biomedical Research, Inc.(HHSN261200800001E). The Brain Bank was supported by University of Miami grant DA006227. Statistical Methods development grants were made to the University of Geneva (MH090941 and MH101814), the University of Chicago (MH090951, MH090937, MH101825, & MH101820), the University of North Carolina—Chapel Hill (MH090936), North Carolina State University (MH101819), Harvard University (MH090948), Stanford University (MH101782), Washington University (MH101810), and to the University of Pennsylvania (MH101822). Publisher Copyright: © 2021, The Author(s).

PY - 2021/12

Y1 - 2021/12

N2 - Mitochondrial dysfunction contributes to the pathogenesis of many neurodegenerative diseases. The mitochondrial genome encodes core respiratory chain proteins, but the vast majority of mitochondrial proteins are nuclear-encoded, making interactions between the two genomes vital for cell function. Here, we examine these relationships by comparing mitochondrial and nuclear gene expression across different regions of the human brain in healthy and disease cohorts. We find strong regional patterns that are modulated by cell-type and reflect functional specialisation. Nuclear genes causally implicated in sporadic Parkinson’s and Alzheimer’s disease (AD) show much stronger relationships with the mitochondrial genome than expected by chance, and mitochondrial-nuclear relationships are highly perturbed in AD cases, particularly through synaptic and lysosomal pathways, potentially implicating the regulation of energy balance and removal of dysfunction mitochondria in the etiology or progression of the disease. Finally, we present MitoNuclearCOEXPlorer, a tool to interrogate key mitochondria-nuclear relationships in multi-dimensional brain data.

AB - Mitochondrial dysfunction contributes to the pathogenesis of many neurodegenerative diseases. The mitochondrial genome encodes core respiratory chain proteins, but the vast majority of mitochondrial proteins are nuclear-encoded, making interactions between the two genomes vital for cell function. Here, we examine these relationships by comparing mitochondrial and nuclear gene expression across different regions of the human brain in healthy and disease cohorts. We find strong regional patterns that are modulated by cell-type and reflect functional specialisation. Nuclear genes causally implicated in sporadic Parkinson’s and Alzheimer’s disease (AD) show much stronger relationships with the mitochondrial genome than expected by chance, and mitochondrial-nuclear relationships are highly perturbed in AD cases, particularly through synaptic and lysosomal pathways, potentially implicating the regulation of energy balance and removal of dysfunction mitochondria in the etiology or progression of the disease. Finally, we present MitoNuclearCOEXPlorer, a tool to interrogate key mitochondria-nuclear relationships in multi-dimensional brain data.

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U2 - https://doi.org/10.1038/s42003-021-02792-w

DO - https://doi.org/10.1038/s42003-021-02792-w

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SN - 2399-3642

VL - 4

JO - Communications Biology

JF - Communications Biology

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ER -

Mitochondrial-nuclear cross-talk in the human brain is modulated by cell type and perturbed in neurodegenerative disease

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