MOTS-c helps reduce inflammation caused by bacterial and viral infections.

[01dragonslayer]

Role of Anti-Inflammatory Mitokines in Aging:​

Mitochondria, immunosenescence and inflammaging: a role for mitokines?

"A global reshaping of the immune responses occurs with ageing, indicated as immunosenescence, where mitochondria and mitochondrial metabolism play an important role. However, much less is known about the role of mitochondrial stress response in this reshaping and in particular of the molecules induced by such response, collectively indicated as mitokines."

"Although many aspects of their biology are still controversial, available data suggest that these mitokines have an anti-inflammatory role and increase with age."

"As far as immune responses other than inflammation, the precise role of mitochondrial stress response and mitokines is less clear, and more studies are needed to better clarify this topic, in particular in the framework of immunosenescence and of the crosstalk between the immune system and other organs such as the liver and adipose tissue. As other types of stresses, like ER stress, can also elicit the production of some mitokines, future studies should disentangle the precise role of mitochondrial dysfunction with respect to other stresses in modulating the immune responses via mitokine production. Moreover, studies aimed at better clarifying the direct responsiveness of mitokines to inflammatory or immunological stimuli would be also desirable. However, should the hypothesis that mitokines are part of an attempt to modulate acute and chronic inflammatory reactions be confirmed, a reappraisal of the biological meaning of their association with morbidity (age-related diseases) and mortality, is urgently needed, also considering their possible use (positive modulation of their expression) as therapeutic tools and targets."

"Thus, all the systems aimed at sensing and responding to mitochondrial dysfunction occupy the centre of the stage for effective adaptation/remodelling of the different cell types and organs involved, leading eventually to either successful or unsuccessful ageing."

"In particular, gain- and loss-of-function experiments in mouse models suggest that GDF15 is a mediator of cancer cachexia. In addition, GDF15 is also considered a marker of all-cause mortality [50, 83], and in agreement in our previous study, we found that, among mitokines, GDF15 is the most associated with mortality in old age. Therefore, the role of GDF15 is more complex than expected and possibly double-sided." (1) (this may be due to inflammation being required for proliferation, at the cost of celluar damage when in excess [citation].)

Anti-Inflammatory Effects of Mitokines:​

"As summarized in the previous paragraphs, GDF15, FGF21 and HN have been proposed as anti-inflammatory molecules in many experimental conditions, in both humans and animal models. As their blood levels appear to increase with age (as many pro-inflammatory mediators do), it is possible that they are part of an integrated, molecular, immune-metabolic machinery/network able to respond to (among others) mitochondrial stress, whose role is to set up a coordinated, systemic anti-inflammatory response in both acute and chronic conditions. In this latter case, the mitokine response could be considered part of an “anti-inflammaging” process whose existence was proposed some years ago as a consequence of inflammaging. In fact, the capability to downregulate both acute and chronic inflammatory responses is crucial to maintain homeostasis in young subjects and to avoid/postpone age-related diseases (CVD, T2D, neuro-inflammation and cancer, among others) in the elderly. Many other anti-inflammatory molecules are known, including resolvins, maresins, adiponectin, IL-10, TGF-β, etc. Some of them are particularly elevated in centenarians, suggesting that these exceptional people owe their longevity, among others, to a successful balancing between pro- and anti-inflammatory mediators."

Mitokines Slow Inflammation Induced Aging, not Aging Caused by Mutated Cells.​

"Now, the discovery that other molecules endowed with anti-inflammatory and immunomodulatory activity increase with age not only in centenarians but also in elderly people suggests that a large, comprehensive anti-inflammaging network is physiologically put in place likely as a general attempt of the ageing organism to cope with the progressive increase of chronic inflammation (inflammaging) and its deleterious effects. However, ultimately this (beneficial) response can be insufficient to counteract the detrimental accumulation with age of molecular insults, particularly in those old people affected by major are-related pathologies. Thus, the increased blood levels of mitokines such as GDF15, FGF21 and HN become correlated with altered haematochemical parameters and lower life expectancy.

A simplified version of this hypothesis is presented in Fig. 1. The key concept expressed in the figure is the balancing between pro- and anti-inflammatory stimuli that are tightly interconnected via feedback loops to produce a net result of detrimental or successful adaptation to a chronic stress."

MOTS-c, The Mitokine. Mitochondria Derived Peptide MOTS-c Suppresses Inflammatory Cytokines:​

"Insulin sensitive tissues, such as skeletal muscle and fat, appear to be key target sites of MOTS-c, and levels of MOTS-c in skeletal muscle and plasma of aged mice are reduced. This has led to speculation that MOTS-c is an age related mitokine... Mitochondrial-derived peptides (MDP), or mitokines, appear to form a critical retrograde communication pathway between the mitochondria and the wider cell, and may have an endocrine cytoprotective role.” (4)

"MOTS-c is a peptide of 16 amino acids discovered few years ago by Lee et al. MOTS-c is expressed in several tissues, such as skeletal muscle and adipose tissue, but it is also present at circulating level, both in mice and humans. Studies suggested that MOTS-c is a key regulator of cellular metabolism and inflammatory processes. It has been shown that MOTS-c counteracts inflammation by reducing the levels of pro-inflammatory cytokines, such as IL-6, IL-1β and TNFα, and increasing those of the anti-inflammatory cytokine IL-10. In particular, MOTS-c decreases the bacterial load in mice with sepsis by enhancing the bactericidal capacity of macrophages and thus improving the survival of mice. Moreover, MOTS-c suppresses inflammation also by controlling NF-κB and STAT1 pathway. As far ageing, it seems that MOTS-c circulating levels decrease with ageing."

"In healthy ageing, stress stimulates the mitochondrial unfolded protein response (UPRmt) and the production of mitokines (HN, FGF21, GDF15) that act to inhibit production and activity of inflammatory cytokines (including IL-1β, IL-18, IL-6, type I IFN, TNF-α) through yet not clarified mechanisms and thus preserve a balance between inflammatory and specific immune responses; in unsuccessful ageing, an imbalance between inflammatory and specific immune responses occurs, with a high production of reactive oxygen species (ROS) and danger-associated molecular patterns (DAMPs) leading to an increase of inflammatory cytokines that contribute to the onset of ARDs."

Mitokines inhibit inflammatory cytokines... mitochondria dysfunction prevents this suppression of inflammatory cytokines, throwing the off the body's balance.

"The antinociceptive effects of MOTS-c were attenuated by the AMPK antagonist compound C. MOTS-c significantly reduced pro-inflammatory cytokine levels and elevated the level of anti-inflammatory cytokine in mouse serum. In addition, MOTS-c treatment significantly increased AMPKα phosphorylation level and suppressed formalin-induced extracellular signal-regulated kinase (ERK), c-Jun amino-terminal kinases (JNK), and P38 activation and c-fos expression in the mouse spinal cord. These results suggest that systemic administration of MOTS-c exerts antinociceptive and anti-inflammatory effects, at least partially, through activating AMPK pathway and inhibiting MAP kinases-c-fos signaling pathway in the mouse formalin test. (3)

Tolerance to Inflammation Induced by Viral or Bacterial Infections:​

"Recently, it has been shown that GDF15 decreases the expression of pro-inflammatory cytokines and prevents the activation of T cells in the liver of mice with fibrosis, while deficiency of GDF15 aggravates liver injury and fibrosis. In agreement, Bootcov and co-workers found that the expression of GDF15 is induced in macrophages by IL-1β, IL-2, TNF-α and TGF-β and limits their activation, consequently blunting inflammation. GDF15 is responsive to inflammation via p53 and is necessary for tolerance to inflammation induced by viral or bacterial infections... plasma GDF15 levels are higher in the elderly, in particular in the presence of pathological conditions, such as CVD, insulin resistance and T2D, neurodegeneration, renal chronic disease and cancer, where it is supposed that GDF15 plays a protective role against different insults via PI3K–Akt, ERK1/2 and SMAD2/3 signalling pathways."

"Sepsis is a life-threatening disease characterized by uncontrolled inflammatory responses upon pathogen infections, especially for the antibiotic-resistant strains, such as Methicillin-resistant S. aureus (MRSA). Here we demonstrated that a Mitochondria-derived peptide (MOTS-c) could significantly improve the survival rate and decrease bacteria loads in MRSA-challenged mice, accompanied with declined levels of pro-inflammatory cytokines, such as TNF-α, IL-6 and IL-1β, but with increased level of anti-inflammatory cytokine IL-10. Moreover this peptide enhanced bactericidal capacity of macrophages. Meanwhile, MOTS-c inhibited the phosphorylation mitogen-activated protein kinases (MAPK), and enhanced the expression of aryl hydrocarbon receptor (AhR) and signal transducer and activator of transcriptional 3 (STAT3) in macrophages. Overall, MOTS-c plays a beneficial role in curbing the overwhelming inflammatory bursts in the fight against MRSA infection. It may serve as a potential therapeutic agent in sepsis treatment.

• MOTS-c improved survival status in mice during MRSA infection.

• MOTS-c strongly enhanced bactericidal capacity of macrophages.

• MOTS-c exerted an anti-inflammatory effect via suppressing MAPKs and increasing Ahr/STAT3 signaling pathways." (2)