Related Experiment Video
Updated: Jun 1, 2025
An In Vitro Approach to Study Mitochondrial Dysfunction: A Cybrid Model
Published on: March 9, 2022
Selective deficiency of mitochondrial respiratory complex I subunits Ndufs4/6 causes tumor immunogenicity
Jiaxin Liang1,2, Tevis Vitale1,2, Xixi Zhang3,4,5
1Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
Abstract:
Cancer cells frequently rewire their metabolism to support proliferation and evade immune surveillance, but little is known about metabolic targets that could increase immune surveillance. Here we show a specific means of mitochondrial respiratory complex I (CI) inhibition that improves tumor immunogenicity and sensitivity to immune checkpoint blockade (ICB). Targeted genetic deletion of either Ndufs4 or Ndufs6, but not other CI subunits, induces an immune-dependent growth attenuation in melanoma and breast cancer models. We show that deletion of Ndufs4 induces expression of the major histocompatibility complex (MHC) class I co-activator Nlrc5 and antigen presentation machinery components, most notably H2-K1. This induction of MHC-related genes is driven by a pyruvate dehydrogenase-dependent accumulation of mitochondrial acetyl-CoA, which leads to an increase in histone H3K27 acetylation within the Nlrc5 and H2-K1 promoters. Taken together, this work shows that selective CI inhibition restricts tumor growth and that specific targeting of Ndufs4 or Ndufs6 increases T cell surveillance and ICB responsiveness.
Insights
Targeting mitochondrial complex I (CI) via Ndufs4 or Ndufs6 deletion enhances anti-tumor immunity. This metabolic approach boosts major histocompatibility complex (MHC) expression, improving cancer cell visibility to T cells and increasing response to immune checkpoint blockade (ICB).
Area of Science:
- Immunology
- Metabolic pathways
- Cancer biology
Background:
- Cancer cells alter metabolism for growth and immune evasion.
- Metabolic targets to enhance immune surveillance are largely unknown.
- Mitochondrial respiratory complex I (CI) plays a role in cellular metabolism.
Purpose of the Study:
- Investigate if inhibiting mitochondrial CI can enhance tumor immunogenicity.
- Determine if specific CI subunits, when deleted, impact tumor growth and immune response.
- Explore the mechanisms by which CI inhibition affects antigen presentation and immune surveillance.
Main Methods:
- Genetic deletion of Ndufs4 and Ndufs6 in melanoma and breast cancer models.
- Analysis of major histocompatibility complex (MHC) class I co-activator Nlrc5 and antigen presentation machinery (H2-K1) expression.
- Assessment of mitochondrial acetyl-CoA levels and histone H3K27 acetylation in target gene promoters.
Main Results:
- Targeted deletion of Ndufs4 or Ndufs6, but not other CI subunits, led to immune-dependent tumor growth attenuation.
- Ndufs4 deletion induced expression of Nlrc5 and H2-K1, enhancing antigen presentation.
- Tumor immunogenicity and sensitivity to immune checkpoint blockade (ICB) were improved by selective CI inhibition.
Conclusions:
- Selective inhibition of mitochondrial CI, specifically Ndufs4 or Ndufs6, restricts tumor growth.
- This metabolic strategy enhances T cell surveillance and responsiveness to ICB.
- Targeting mitochondrial metabolism offers a novel approach to augment anti-cancer immunity.
Related Concept Videos
01:46Electron Transport Chain: Complex I and II
ROS generation is regulated and maintained at moderate levels necessary...
01:30The Electron Transport Chain
Inhibitors of the electron transport chain
Rotenone, a widely used pesticide, prevents electron transfer from Fe-S cluster to ubiquinone or Q...
01:48ATP Synthase: Mechanism