Frataxin deficiency impairs mitochondrial biogenesis in cells, mice and humans

Mittal J. Jasoliya, Marissa Z. McMackin, Chelsea K. Henderson, Susan L. Perlman, Gino A Cortopassi

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Friedreich's ataxia (FRDA) is a neurodegenerative disease caused by inherited deficiency of the mitochondrial protein Frataxin (FXN), which has no approved therapy and is an area in which biomarkers are needed for clinical development. Here, we investigated the consequences of FXN deficiency in patient-derived FRDA fibroblast cell models, the FRDA mouse model KIKO, and in whole blood collected from patients with FRDA. We observed decreased mitochondrial copy number in all the three FRDA models tested: cells, mice and patient blood. In addition, we observed 40% residual mitochondrial gene expression in FRDA patient blood. These deficiencies of mitochondrial biogenesis in FRDA cells and patient blood are significantly correlated with FXN expression, consistent with the idea that the decreased mitochondrial biogenesis is a consequence of FXN deficiency. The observations appear relevant to the FRDA pathophysiological mechanism, as FXN-dependent deficiency in mitochondrial biogenesis and consequent mitochondrial bioenergetic defect could contribute to the neurodegenerative process. The observations may also have translational potential, as mitochondrial biogenesis could now be followed as a clinical biomarker of FRDA as a correlate of disease severity, progression, and therapeutic effect. Also, mitochondrial copy number in blood is objective, scalar and more investigator-independent than clinical-neurological patient rating scales. Thus, FXN deficiency causes mitochondrial deficiency in FRDA cells, the KIKO mouse model, and in whole blood of patients with FRDA, and this deficiency could potentially be used in clinical trial design.

Original languageEnglish (US)
Pages (from-to)2627-2633
Number of pages7
JournalHuman Molecular Genetics
Volume26
Issue number14
DOIs
StatePublished - Jul 15 2017

Fingerprint

Friedreich Ataxia
Organelle Biogenesis
frataxin
Biomarkers
Mitochondrial Genes
Mitochondrial Proteins
Therapeutic Uses
Neurodegenerative Diseases
Energy Metabolism
Disease Progression
Blood Cells
Fibroblasts

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Frataxin deficiency impairs mitochondrial biogenesis in cells, mice and humans. / Jasoliya, Mittal J.; McMackin, Marissa Z.; Henderson, Chelsea K.; Perlman, Susan L.; Cortopassi, Gino A.

In: Human Molecular Genetics, Vol. 26, No. 14, 15.07.2017, p. 2627-2633.

Research output: Contribution to journalArticle

Jasoliya, Mittal J. ; McMackin, Marissa Z. ; Henderson, Chelsea K. ; Perlman, Susan L. ; Cortopassi, Gino A. / Frataxin deficiency impairs mitochondrial biogenesis in cells, mice and humans. In: Human Molecular Genetics. 2017 ; Vol. 26, No. 14. pp. 2627-2633.
@article{e631cefb50c7499dbdce724cad217a13,
title = "Frataxin deficiency impairs mitochondrial biogenesis in cells, mice and humans",
abstract = "Friedreich's ataxia (FRDA) is a neurodegenerative disease caused by inherited deficiency of the mitochondrial protein Frataxin (FXN), which has no approved therapy and is an area in which biomarkers are needed for clinical development. Here, we investigated the consequences of FXN deficiency in patient-derived FRDA fibroblast cell models, the FRDA mouse model KIKO, and in whole blood collected from patients with FRDA. We observed decreased mitochondrial copy number in all the three FRDA models tested: cells, mice and patient blood. In addition, we observed 40{\%} residual mitochondrial gene expression in FRDA patient blood. These deficiencies of mitochondrial biogenesis in FRDA cells and patient blood are significantly correlated with FXN expression, consistent with the idea that the decreased mitochondrial biogenesis is a consequence of FXN deficiency. The observations appear relevant to the FRDA pathophysiological mechanism, as FXN-dependent deficiency in mitochondrial biogenesis and consequent mitochondrial bioenergetic defect could contribute to the neurodegenerative process. The observations may also have translational potential, as mitochondrial biogenesis could now be followed as a clinical biomarker of FRDA as a correlate of disease severity, progression, and therapeutic effect. Also, mitochondrial copy number in blood is objective, scalar and more investigator-independent than clinical-neurological patient rating scales. Thus, FXN deficiency causes mitochondrial deficiency in FRDA cells, the KIKO mouse model, and in whole blood of patients with FRDA, and this deficiency could potentially be used in clinical trial design.",
author = "Jasoliya, {Mittal J.} and McMackin, {Marissa Z.} and Henderson, {Chelsea K.} and Perlman, {Susan L.} and Cortopassi, {Gino A}",
year = "2017",
month = "7",
day = "15",
doi = "10.1093/hmg/ddx141",
language = "English (US)",
volume = "26",
pages = "2627--2633",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "14",

}

TY - JOUR

T1 - Frataxin deficiency impairs mitochondrial biogenesis in cells, mice and humans

AU - Jasoliya, Mittal J.

AU - McMackin, Marissa Z.

AU - Henderson, Chelsea K.

AU - Perlman, Susan L.

AU - Cortopassi, Gino A

PY - 2017/7/15

Y1 - 2017/7/15

N2 - Friedreich's ataxia (FRDA) is a neurodegenerative disease caused by inherited deficiency of the mitochondrial protein Frataxin (FXN), which has no approved therapy and is an area in which biomarkers are needed for clinical development. Here, we investigated the consequences of FXN deficiency in patient-derived FRDA fibroblast cell models, the FRDA mouse model KIKO, and in whole blood collected from patients with FRDA. We observed decreased mitochondrial copy number in all the three FRDA models tested: cells, mice and patient blood. In addition, we observed 40% residual mitochondrial gene expression in FRDA patient blood. These deficiencies of mitochondrial biogenesis in FRDA cells and patient blood are significantly correlated with FXN expression, consistent with the idea that the decreased mitochondrial biogenesis is a consequence of FXN deficiency. The observations appear relevant to the FRDA pathophysiological mechanism, as FXN-dependent deficiency in mitochondrial biogenesis and consequent mitochondrial bioenergetic defect could contribute to the neurodegenerative process. The observations may also have translational potential, as mitochondrial biogenesis could now be followed as a clinical biomarker of FRDA as a correlate of disease severity, progression, and therapeutic effect. Also, mitochondrial copy number in blood is objective, scalar and more investigator-independent than clinical-neurological patient rating scales. Thus, FXN deficiency causes mitochondrial deficiency in FRDA cells, the KIKO mouse model, and in whole blood of patients with FRDA, and this deficiency could potentially be used in clinical trial design.

AB - Friedreich's ataxia (FRDA) is a neurodegenerative disease caused by inherited deficiency of the mitochondrial protein Frataxin (FXN), which has no approved therapy and is an area in which biomarkers are needed for clinical development. Here, we investigated the consequences of FXN deficiency in patient-derived FRDA fibroblast cell models, the FRDA mouse model KIKO, and in whole blood collected from patients with FRDA. We observed decreased mitochondrial copy number in all the three FRDA models tested: cells, mice and patient blood. In addition, we observed 40% residual mitochondrial gene expression in FRDA patient blood. These deficiencies of mitochondrial biogenesis in FRDA cells and patient blood are significantly correlated with FXN expression, consistent with the idea that the decreased mitochondrial biogenesis is a consequence of FXN deficiency. The observations appear relevant to the FRDA pathophysiological mechanism, as FXN-dependent deficiency in mitochondrial biogenesis and consequent mitochondrial bioenergetic defect could contribute to the neurodegenerative process. The observations may also have translational potential, as mitochondrial biogenesis could now be followed as a clinical biomarker of FRDA as a correlate of disease severity, progression, and therapeutic effect. Also, mitochondrial copy number in blood is objective, scalar and more investigator-independent than clinical-neurological patient rating scales. Thus, FXN deficiency causes mitochondrial deficiency in FRDA cells, the KIKO mouse model, and in whole blood of patients with FRDA, and this deficiency could potentially be used in clinical trial design.

UR - http://www.scopus.com/inward/record.url?scp=85034019349&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85034019349&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddx141

DO - 10.1093/hmg/ddx141

M3 - Article

C2 - 28444186

AN - SCOPUS:85034019349

VL - 26

SP - 2627

EP - 2633

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 14

ER -