Related Experiment Video

Updated: Aug 7, 2025

Measuring Mitochondrial Function of Naïve and Effector CD8 T Cells
06:07

Measuring Mitochondrial Function of Naïve and Effector CD8 T Cells

Published on: March 28, 2025

388

Fumarate induces vesicular release of mtDNA to drive innate immunity

Vincent Zecchini1, Vincent Paupe2, Irene Herranz-Montoya1,3

  • 1Medical Research Council Cancer Unit, University of Cambridge, Cambridge, UK.

Nature
|March 8, 2023
PubMed

Insights

Loss of fumarate hydratase (FH) triggers early kidney cell inflammation by releasing mitochondrial DNA. This innate immune response is mediated by fumarate accumulation and mitochondrial changes.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Oncology

Background:

  • Mutations in fumarate hydratase (FH) are linked to hereditary leiomyomatosis and renal cell carcinoma.
  • FH loss in kidneys causes oncogenic signaling via fumarate accumulation, but the acute response remains unclear.

Purpose of the Study:

  • To investigate the acute cellular response to fumarate hydratase loss in the kidney.
  • To elucidate the molecular mechanisms underlying the early stages of FH-deficient renal cell carcinoma development.

Main Methods:

  • Generation of an inducible mouse model for studying FH loss chronology in the kidney.
  • Analysis of mitochondrial morphology, mitochondrial DNA release, and innate immune pathway activation (cGAS-STING-TBK1, RIG-I).
  • Investigation of fumarate's role and the involvement of mitochondrial-derived vesicles and sorting nexin 9 (SNX9).

Main Results:

  • FH loss rapidly alters mitochondrial morphology and releases mitochondrial DNA (mtDNA) into the cytosol.
  • Cytosolic mtDNA activates the cGAS-STING-TBK1 and RIG-I innate immune pathways, inducing inflammation.
  • Fumarate mediates this response through SNX9-dependent mitochondrial-derived vesicles.

Conclusions:

  • Acute FH loss triggers an innate immune response in kidney cells via fumarate-induced mtDNA release.
  • This study reveals a novel mechanism linking metabolic dysfunction to immune activation in renal cell carcinoma pathogenesis.
  • Targeting fumarate accumulation or mitochondrial dynamics may offer therapeutic strategies for FH-related cancers.

More Related Videos

Methods to Evaluate Cytotoxicity and Immunosuppression of Combustible Tobacco Product Preparations09:25

Methods to Evaluate Cytotoxicity and Immunosuppression of Combustible Tobacco Product Preparations

Published on: January 10, 2015

11.5K
F1FO ATPase Vesicle Preparation and Technique for Performing Patch Clamp Recordings of Submitochondrial Vesicle Membranes08:21

F1FO ATPase Vesicle Preparation and Technique for Performing Patch Clamp Recordings of Submitochondrial Vesicle Membranes

Published on: May 4, 2013

10.4K

Related Concept Videos

Animal Mitochondrial Genetics02:59

Animal Mitochondrial Genetics

Among all the organelles in an animal cell, only mitochondria have their own independent genomes. Animal mitochondrial DNA is a double-stranded, closed-circular molecule with around 20,000 base pairs. Mitochondrial DNA is unique in that one of its two strands, the heavy, or H, -strand is guanine rich, whereas the complementary strand is cytosine rich and called the light, or L, -strand. Compared to nuclear DNA, mitochondrial DNA has a very low percentage of non-coding regions and is marked by...
7.7K
Translocation of Proteins into the Mitochondria01:19

Translocation of Proteins into the Mitochondria

Mitochondrial precursors are translocated to the internal subcompartments via independent mechanisms involving distinct protein machineries called translocases.
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
3.2K
Cystic Fibrosis: Pathogenesis01:23

Cystic Fibrosis: Pathogenesis

Cystic fibrosis (CF), an autosomal recessive disorder, significantly affects the function of exocrine glands. This genetically inherited disease is characterized by the production of thick and sticky mucus, which can severely affect various organs and systems in the body.
CF is primarily caused by a genetic mutation in a chromosome 7 gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The most common gene mutation leading to CF is the ΔF508 mutation,...
320
The Inner Mitochondrial Membrane01:28

The Inner Mitochondrial Membrane

The inner mitochondrial membrane is the primary site of ATP synthesis. The inner membrane domain that forms a smooth layer adjacent to the outer membrane is called the inner boundary membrane. This domain contains membrane transporters that drive metabolites in and out of the mitochondria.  In contrast, the inner membrane network that invaginates into the matrix space is called the cristae membrane. This domain accounts for principle mitochondrial function as it accommodates the protein...
3.5K
Mitochondrial Membranes01:45

Mitochondrial Membranes

A single mitochondrion is a bean-shaped organelle enclosed by a double-membrane system. The outer membrane of mitochondria is smooth and contains many porins - the integral membrane transporters. Porins enable free diffusion of ions and small uncharged molecules through the outer mitochondrial membrane but limit the transport of molecules larger than 5000 Daltons. Further, the outer mitochondrial membrane forms a unique structure called membrane contact sites with other subcellular organelles,...
11.7K