Dataset Information

Genetic therapy in a mitochondrial disease model suggests a critical role for liver dysfunction in mortality.

ABSTRACT: The clinical and largely unpredictable heterogeneity of phenotypes in patients with mitochondrial disorders demonstrates the ongoing challenges in the understanding of this semi-autonomous organelle in biology and disease. Previously, we used the gene-breaking transposon to create 1200 transgenic zebrafish strains tagging protein-coding genes (Ichino et al., 2020), including the lrpprc locus. Here, we present and characterize a new genetic revertible animal model that recapitulates components of Leigh Syndrome French Canadian Type (LSFC), a mitochondrial disorder that includes diagnostic liver dysfunction. LSFC is caused by allelic variations in the LRPPRC gene, involved in mitochondrial mRNA polyadenylation and translation. lrpprc zebrafish homozygous mutants displayed biochemical and mitochondrial phenotypes similar to clinical manifestations observed in patients, including dysfunction in lipid homeostasis. We were able to rescue these phenotypes in the disease model using a liver-specific genetic model therapy, functionally demonstrating a previously under-recognized critical role for the liver in the pathophysiology of this disease.

SUBMITTER: Sabharwal A

PROVIDER: S-EPMC9859037 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Genetic therapy in a mitochondrial disease model suggests a critical role for liver dysfunction in mortality.

Sabharwal Ankit A Wishman Mark D MD Cervera Roberto Lopez RL Serres MaKayla R MR Anderson Jennifer L JL Holmberg Shannon R SR Kar Bibekananda B Treichel Anthony J AJ Ichino Noriko N Liu Weibin W Yang Jingchun J Ding Yonghe Y Deng Yun Y Lacey Jean M JM Laxen William J WJ Loken Perry R PR Oglesbee Devin D Farber Steven A SA Clark Karl J KJ Xu Xiaolei X Ekker Stephen C SC

eLife 20221121

The clinical and largely unpredictable heterogeneity of phenotypes in patients with mitochondrial disorders demonstrates the ongoing challenges in the understanding of this semi-autonomous organelle in biology and disease. Previously, we used the gene-breaking transposon to create 1200 transgenic zebrafish strains tagging protein-coding genes (Ichino et al., 2020), including the <i>lrpprc</i> locus. Here, we present and characterize a new genetic revertible animal model that recapitulates compon ...[more]

PMID: 36408801

Similar Datasets

Project description:Mitochondria are entrusted with the challenging task of providing energy through the generation of ATP, the universal cellular currency, thereby being highly flexible to different acute and chronic nutrient demands of the cell. The fact that mitochondrial diseases (genetic disorders caused by mutations in the nuclear or mitochondrial genome) manifest through a remarkable clinical variation of symptoms in affected individuals underlines the far-reaching implications of mitochondrial dysfunction. The study of mitochondrial function in genetic or non-genetic diseases therefore requires a multi-angled approach. Taking into account that the liver is among the organs richest in mitochondria, it stands to reason that in the process of unravelling the pathogenesis of liver-related diseases, researchers give special focus to characterizing mitochondrial function. However, mitochondrial dysfunction is not a uniformly defined term. It can refer to a decline in energy production, increase in reactive oxygen species and so forth. Therefore, any study on mitochondrial dysfunction first needs to define the dysfunction to be investigated. Here, we review the alterations of mitochondrial function in liver cirrhosis with emphasis on acutely decompensated liver cirrhosis and acute-on-chronic liver failure (ACLF), the latter being a form of acute decompensation characterized by a generalized state of systemic hyperinflammation/immunosuppression and high mortality rate. The studies that we discuss were either carried out in liver tissue itself of these patients, or in circulating leukocytes, whose mitochondrial alterations might reflect tissue and organ mitochondrial dysfunction. In addition, we present different methodological approaches that can be of utility to address the diverse aspects of hepatocyte and leukocyte mitochondrial function in liver disease. They include assays to measure metabolic fluxes using the comparatively novel Biolog's MitoPlates in a 96-well format as well as assessment of mitochondrial respiration by high-resolution respirometry using Oroboros' O2k-technology and Agilent Seahorse XF technology.

Dataset Information

Genetic therapy in a mitochondrial disease model suggests a critical role for liver dysfunction in mortality.

Publications

Genetic therapy in a mitochondrial disease model suggests a critical role for liver dysfunction in mortality.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets