Experimental evidence that mutated-self peptides derived from mitochondrial DNA somatic mutations have the potential to trigger autoimmunity

Chen, Lina; Duvvuri, Bhargavi; Grigull, Jörg; Jamnik, Roni; Wither, Joan E.; Wu, Gillian E.

doi:10.1016/j.humimm.2014.06.012

Cited by 18 publications

(31 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…112 Indeed the mutations of mtDNA are shown to be a possible source of immunogenic self-peptides initiating the T cell-mediated immune responses. 113,114 Autophagy can produce the antigenic peptides conjugated with both MHCI and MHCII molecules, 115,116 but antigen presentation mechanisms activated in mitophagy are different. Mitophagy activators PINK1 and Parkin do not activate, but in contrary, suppress mitochondrial antigens presentation (MitAP).…”

Section: Turnover Of Mitochondriamentioning

confidence: 99%

“…Chen et al suggested that somatically mutated self-proteins are involved in autoimmune disease development. 113 To demonstrate their hypothesis, PBMCs were collected from healthy donors and autoimmune patients with systemic lupus erythematosus or ankylosing spondylitis, T cells were stimulated with either mitochondrial self-peptides or mitochondria-mutated peptides; T cells activated by the mutated self-peptide were cross-reactive with the self-peptide both in healthy and autoimmune patients as measured by IFNγ levels. 113 This study suggests that somatic mutations may participate in the induction of autoimmune diseases by antigen presentation.…”

Section: Turnover Of Mitochondriamentioning

confidence: 99%

“…113 To demonstrate their hypothesis, PBMCs were collected from healthy donors and autoimmune patients with systemic lupus erythematosus or ankylosing spondylitis, T cells were stimulated with either mitochondrial self-peptides or mitochondria-mutated peptides; T cells activated by the mutated self-peptide were cross-reactive with the self-peptide both in healthy and autoimmune patients as measured by IFNγ levels. 113 This study suggests that somatic mutations may participate in the induction of autoimmune diseases by antigen presentation. Interestingly, many different types of cancers harbor somatic mitochondrial DNA mutations 117,177,178 and consequently an increased immune response has been observed against mutated mitochondrial peptides; for example, mitochondrial cytochrome b peptide derived from melanoma cells of patients is recognized by CD4+ T cells.…”

Section: Turnover Of Mitochondriamentioning

confidence: 99%

See 2 more Smart Citations

Targeting mitochondria in cancer: current concepts and immunotherapy approaches

Pustylnikov

Costabile

Beghi

et al. 2018

Translational Research

114

View full text Add to dashboard Cite

An essential advantage during eukaryotic cell evolution was the acquisition of a network of mitochondria as a source of energy for cell metabolism and contrary to conventional wisdom, functional mitochondria are essential for the cancer cell. Multiple aspects of mitochondrial biology beyond bioenergetics support transformation including mitochondrial biogenesis, fission and fusion dynamics, cell death susceptibility, oxidative stress regulation, metabolism, and signaling. In cancer, the metabolism of cells is reprogrammed for energy generation from oxidative phosphorylation to aerobic glycolysis and impacts cancer mitochondrial function. Furthermore cancer cells can also modulate energy metabolism within the cancer microenvironment including immune cells and induce "metabolic anergy" of antitumor immune response. Classical approaches targeting the mitochondria of cancer cells usually aim at inducing changing energy metabolism or directly affecting functions of mitochondrial antiapoptotic proteins but most of such approaches miss the required specificity of action and carry important side effects. Several types of cancers harbor somatic mitochondrial DNA mutations and specific immune response to mutated mitochondrial proteins has been observed. An attractive alternative way to target the mitochondria in cancer cells is the induction of an adaptive immune response against mutated mitochondrial proteins. Here, we review the cancer cell-intrinsic and cell-extrinsic mechanisms through which mitochondria influence all steps of oncogenesis, with a focus on the therapeutic potential of targeting mitochondrial DNA mutations or Tumor Associated Mitochondria Antigens using the immune system.

show abstract

Section: Turnover Of Mitochondriamentioning

confidence: 99%

Section: Turnover Of Mitochondriamentioning

confidence: 99%

Section: Turnover Of Mitochondriamentioning

confidence: 99%

See 1 more Smart Citation

Targeting mitochondria in cancer: current concepts and immunotherapy approaches

Pustylnikov

Costabile

Beghi

et al. 2018

Translational Research

114

View full text Add to dashboard Cite

show abstract

“…Mitochondria play an important role in the immune system, which involves signaling platforms, effector responses [ 12 ], and modulating the antigen-specific T cell activation via reactive oxygen species (ROS) signaling [ 13 , 14 ]. Mitochondrial antigens, such as M2 autoantigens [ 15 ], oxo-acid dehydrogenase complexes [ 16 ] and 2-oxoglutarate dehydrogenase complex [ 17 ], are known to induce disease-related autoimmune responses such as primary biliary cirrhosis (PBC) [ 15 , 16 , 17 , 18 , 19 ]. The targets located in the different compartments of mitochondria for possible vaccine development are listed in Table 1 .…”

Section: Introductionmentioning

confidence: 99%

Mitochondrion: A Promising Target for Nanoparticle-Based Vaccine Delivery Systems

et al. 2016

View full text Add to dashboard Cite

Vaccination is one of the most popular technologies in disease prevention and eradication. It is promising to improve immunization efficiency by using vectors and/or adjuvant delivery systems. Nanoparticle (NP)-based delivery systems have attracted increasing interest due to enhancement of antigen uptake via prevention of vaccine degradation in the biological environment and the intrinsic immune-stimulatory properties of the materials. Mitochondria play paramount roles in cell life and death and are promising targets for vaccine delivery systems to effectively induce immune responses. In this review, we focus on NPs-based delivery systems with surfaces that can be manipulated by using mitochondria targeting moieties for intervention in health and disease.

show abstract

“…Mitochondrial Ags are presented to and recognized by the immune system, and there is evidence that mitochondrial peptides may participate in the induction of autoimmune diseases (8,9). For example, autoreactive T cell responses to peptides derived from the pyruvate dehydrogenase complex are found in almost all cirrhosis patients (10).…”

mentioning

confidence: 99%

A Tumor Mitochondria Vaccine Protects against Experimental Renal Cell Carcinoma

Pierini

Fang

Rafail

et al. 2015

The Journal of Immunology

View full text Add to dashboard Cite

Mitochondria provide energy for cells via oxidative phosphorylation. Reactive oxygen species, a byproduct of this mitochondrial respiration, can damage mitochondrial DNA (mtDNA), and somatic mtDNA mutations have been found in all colorectal, ovarian, breast, urinary bladder, kidney, lung, and pancreatic tumors studied. The resulting altered mitochondrial proteins or tumor-associated mitochondrial Ags (TAMAs) are potentially immunogenic, suggesting that they may be targetable Ags for cancer immunotherapy. In this article, we show that the RENCA tumor cell line harbors TAMAs that can drive an antitumor immune response. We generated a cellular tumor vaccine by pulsing dendritic cells with enriched mitochondrial proteins from RENCA cells. Our dendritic cell–based RENCA mitochondrial lysate vaccine elicited a cytotoxic T cell response in vivo and conferred durable protection against challenge with RENCA cells when used in a prophylactic or therapeutic setting. By sequencing mtDNA from RENCA cells, we identified two mutated molecules: COX1 and ND5. Peptide vaccines generated from mitochondrial-encoded COX1 but not from ND5 had therapeutic properties similar to RENCA mitochondrial protein preparation. Thus, TAMAs can elicit effective antitumor immune responses, potentially providing a new immunotherapeutic strategy to treat cancer.

show abstract

Experimental evidence that mutated-self peptides derived from mitochondrial DNA somatic mutations have the potential to trigger autoimmunity

Cited by 18 publications

References 41 publications

Targeting mitochondria in cancer: current concepts and immunotherapy approaches

Targeting mitochondria in cancer: current concepts and immunotherapy approaches

Mitochondrion: A Promising Target for Nanoparticle-Based Vaccine Delivery Systems

A Tumor Mitochondria Vaccine Protects against Experimental Renal Cell Carcinoma

Contact Info

Product

Resources

About