A multidisciplinary team of researchers from Duke-NUS Medical School and the Agency for Science, Technology and Research (A*STAR) in Singapore has discovered a new mitochondrial peptide called MOCCI that plays an important role in regulating inflammation of blood vessel and immunity.
The study, published in the journal Nature Communications, revealed how one gene encoded two molecules that provide two-pronged protection following viral infection.
Chronic and excessive inflammation of the blood vessels, known as vascular inflammation, can lead to tissue damage and cardiovascular diseases such as atherosclerosis and fibrosis. Although some therapies have shown promising results in clinical trials, they have considerable side effects, such as immunosuppression leading to increased risk of infection, and limited efficacy. Therefore, more effective treatments are urgently needed.
“In this study, we aimed to identify new targets to combat inflammation in the lining of blood vessels. Specifically, we wanted to target small naturally-produced peptides that have not been studied before,” explained Assistant Professor Lena Ho, from the Cardiovascular and Metabolic Disorders Program at Duke-NUS, who led the team that included Associate Professor Ashley St John, Assistant Professor Owen Rackham and Senior Research Fellow Dr. Cheryl Lee.
The Duke-NUS team, in collaboration with colleagues from the Institute of Molecular and Cell Biology at A*STAR Singapore, investigated a group of peptides called Mito-SEPs that localise in mitochondria, the cellular organelles well-known for their role in cellular energy production.
After observing that Mito-SEPs appear to be involved in regulating inflammation, they screened cells from the lining of human aortic blood vessels to uncover peptides involved in this process.
They found a new peptide, which they named MOCCI – short for Modulator of Cytochrome C oxidase during Inflammation – that is made only when cells undergo inflammation and infection.
To their surprise, they discovered that MOCCI is a hitherto unknown component of Complex IV, a part of a series of enzymes in the mitochondria responsible for energy production, called the electron transport chain. During inflammation, MOCCI incorporates into Complex IV to dampen its activity.
Collaborating with Assoc Prof St John at Duke-NUS, the researchers found that this dampening is required to reduce inflammation following viral infection.
“Our finding that the composition of the electron transport chain changes in response to inflammation is novel. MOCCI in essence repurposes part of the energy production center in the cell to regulate inflammation,” said Dr. Lee, the lead author of this study.
The researchers also discovered that MOCCI is made together with a micro-RNA molecule called miR-147b. The two molecules are made from different sections of the same gene. MOCCI originates from the sequence of the gene that codes for proteins, while miR-147b is made from the non-coding section.
While the miR-147b molecule also exerts anti-inflammatory effects, it actively prevents viruses from replicating at the same time. This implies that MOCCI and miR-147b function in tandem to help to control viral infection and suppress inflammation.
“This dual-pronged strategy is an elegant mechanism that the body has put in place to prevent excessive and potentially tissue-damaging inflammation during infection, such as the cytokine storm seen in COVID-19 infection, and colitis” said Asst Prof Ho.
“The gene encoding MOCCI is one of the first genes described to have both coding and non-coding functions. The fact these dual functions are coordinated to achieve a concerted biological outcome is a significant finding in cell biology.”
Professor Patrick Casey, senior vice-dean for research at Duke-NUS, said, “Medicine and healthcare advance with the aid of new discoveries in fundamental research. This study by Asst Prof Ho and her collaborators provides valuable insight on inflammation and immunity—a topic that has become even more important in the context of COVID-19.”
The researchers say the next step is to explore how to develop targeted pharmacological treatments that can mimic the anti-inflammatory effects of MOCCI and miR147b. They also plan to investigate the role of MOCCI in common chronic inflammatory diseases such as colitis and psoriasis.
Activation of the endothelium by inflammatory triggers initiates a cascade of signaling pathways with the aim of danger signal clearance and resolution of the inflammatory response, ultimately returning the endothelium to its basal state1. Failure to do so results in excessive vascular inflammation that leads to tissue damage in acute settings, and cardiovascular diseases such as atherosclerosis and fibrosis in chronic settings.
Although broad immunosuppressive strategies such as tumor necrosis factor-alpha (α), interleukin-1beta (IL-1β), or interleukin-6 (IL-6) blockade with neutralizing antibodies have yielded promising results in clinical trials to reduce vascular inflammation2, their considerable side effects and limited efficacy indicate a need for alternative, more specific targets, potentially downstream of these cytokines, and preferably specific to the endothelium.
Mitochondria are multifaceted organelles most well-known for their roles in cellular energy production via oxidative phosphorylation and in apoptosis via cytochrome c release. Besides energetic homeostasis, the role of mitochondria in regulating the onset and outcomes of inflammation is becoming increasingly appreciated3.
A classic example is the production of reactive oxygen species (ROS) from the respiratory chain. Once thought to be purely pathogenic, it is now appreciated that low or physiological levels of ROS play normative roles in both pro-inflammatory and pro-resolving signaling pathways, while excessive ROS can lead to chronic activation of pro-inflammatory mechanisms that cause tissue damage4.
The mitochondria are also known to be a proximal site for the activation of interferon response (IR) via the localization of MAVS5 or the activation of inflammasome via the extrusion of cardiolipin6. Leakage of mitochondrial DNA can also trigger IR or inflammatory cell death through the c-GAS/STING pathway7.
Furthermore, metabolites of the Krebs cycle such as succinate and itaconate are increasingly recognized as modulators of inflammation; for example, through the regulation of the NLRP3 inflammasome and the IR pathway8,9. Although mitochondrial dysfunction is widely implicated in the pathogenesis of cardiovascular diseases, the specific function of mitochondria in endothelial health and dysfunction has received relatively little attention. In particular, how endothelial mitochondria respond to and modulate an inflammatory response is poorly understood.
Previously, our lab reported a preponderance of small open reading frame (sORF)-encoded peptides, defined as proteins smaller than 100 residues that localize to the mitochondria (mito-SEPs)10. These peptides have functions in diverse processes in the mitochondria, including electron transport, lipid metabolism, and calcium homeostasis.
We asked the question of whether mito-SEPs might play hitherto unappreciated roles in regulating inflammation. For instance, Fitzgerald and colleagues recently identified a mitochondrial peptide Mm47 that is required for the activation of the NLRP3 inflammasome11.
In this study, we perform a proteogenomic screen to find mito-SEPs in primary human aortic endothelial cells (HAECs) that can promote the resolution of inflammation. We report the discovery of modulator of cytochrome C oxidase during Inflammation (MOCCI), a mito-SEP encoded by C15ORF48. In concert with miR-147b in the 3′ untranslated region (UTR) of C15ORF48, MOCCI replaces its paralog NDUFA4 in Complex IV (CIV).
This dampens CIV activity and protects host tissue against excessive immune pathology by reducing cell death and cytokine production. Furthermore, miR-147b exerts potent antiviral effects by enhancing the IR through the RIG-I/MDA5 pathway.
Altogether, the coding and non-coding functions of the C15ORF48 synergize to protect the host during infection, illustrating how small peptides coordinate with their encoding transcripts to achieve maximal biological impact.
reference link: https://www.nature.com/articles/s41467-021-22397-5
More information: Cheryl Q. E. Lee et al. Coding and non-coding roles of MOCCI (C15ORF48) coordinate to regulate host inflammation and immunity, Nature Communications (2021). DOI: 10.1038/s41467-021-22397-5
