Comparative effects of 3,5-diiodo-L-thyronine and 3,5,3'-triiodo-L-thyronine on mitochondrial damage and cGAS/STING-driven inflammation in liver of hypothyroid rats.

Maintaining a well-functioning mitochondrial network through the mitochondria quality control (MQC) mechanisms, including biogenesis, dynamics and mitophagy, is crucial for overall health. Mitochondrial dysfunction caused by oxidative stress and further exacerbated by impaired quality control can trigger inflammation through the release of the damage-associated molecular patterns (mtDAMPs). mtDAMPs act by stimulating the cyclic GMP-AMP synthase (cGAS) stimulator of interferon genes (STING) pathway. Recently, aberrant signalling of the cGAS-STING axis has been recognised to be closely associated with several sterile inflammatory diseases (e.g. non-alcoholic fatty liver disease, obesity). This may fit the pathophysiology of hypothyroidism, an endocrine disorder characterised by the reduction of thyroid hormone production associated with impaired metabolic fluxes, oxidative balance and inflammatory status. Both 3,5,3'-triiodo-L-tyronine (T3) and its derivative 3,5-diiodo-L-thyronine (3,5-T2), are known to mitigate processes targeting mitochondria, albeit the underlying mechanisms are not yet fully understood. Therefore, we used a chemically induced hypothyroidism rat model to investigate the effect of 3,5-T2 or T3 administration on inflammation-related factors (inflammatory cytokines, hepatic cGAS-STING pathway), oxidative stress, antioxidant defence enzymes, mitochondrial DNA (mtDNA) damage, release and repair, and the MQC system in the liver. Hypothyroid rats showed: i) increased oxidative stress, ii) accumulation of mtDNA damage, iii) high levels of circulating cytokines, iv) hepatic activation of cGAS-STING pathways and v) impairment of MQC mechanisms and autophagy. Both iodothyronines restored oxidative balance by enhancing antioxidant defence, preventing mtDNA damage through the activation of mtDNA repair mechanisms (OGG1, APE1, and POLγ) and promoting autophagy progression. Concerning MQC, both iodothyronines stimulated mitophagy and dynamics, with 3,5-T2 activating fusion and T3 modulating both fusion and fission processes. Moreover, only T3 enhanced mitochondrial biogenesis. Notably, 3,5-T2, but not T3, reversed the hypothyroidism-induced activation of the cGAS-STING inflammatory cascade. In addition, it is noteworthy that 3,5-T2 seems more effective than T3 in reducing circulating pro-inflammatory cytokines IL-6 and IL-1B and in stimulating the release of IL-10, a known anti-inflammatory cytokine. These findings reveal novel molecular mechanisms of hepatic signalling pathways involved in hypothyroidism, which could be targeted by natural iodothyronines, particularly 3,5-T2, paving the way for the development of new treatment strategies for inflammatory diseases.

Mitochondrial Dysfunction is a Crucial Immune Checkpoint for Neuroinflammation and Neurodegeneration: mtDAMPs in Focus.

Neuroinflammation is a pivotal factor in the progression of both age-related and acute neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and stroke. Mitochondria, essential for neuronal health due to their roles in energy production, calcium buffering, and oxidative stress regulation, become increasingly susceptible to dysfunction under conditions of metabolic stress, aging, or injury. Impaired mitophagy in aged or injured neurons leads to the accumulation of dysfunctional mitochondria, which release mitochondrial-derived damage-associated molecular patterns (mtDAMPs). These mtDAMPs act as immune checkpoints, activating pattern recognition receptors (PRRs) and triggering innate immune signaling pathways. This activation initiates inflammatory responses in neurons and brain-resident immune cells, releasing cytokines and chemokines that damage adjacent healthy neurons and recruit peripheral immune cells, further amplifying neuroinflammation and neurodegeneration. Long-term mitochondrial dysfunction perpetuates a chronic inflammatory state, exacerbating neuronal injury and contributing additional immunogenic components to the extracellular environment. Emerging evidence highlights the critical role of mtDAMPs in initiating and sustaining neuroinflammation, with circulating levels of these molecules potentially serving as biomarkers for disease progression. This review explores the mechanisms of mtDAMP release due to mitochondrial dysfunction, their interaction with PRRs, and the subsequent activation of inflammatory pathways. We also discuss the role of mtDAMP-triggered innate immune responses in exacerbating both acute and chronic neuroinflammation and neurodegeneration. Targeting dysfunctional mitochondria and mtDAMPs with pharmacological agents presents a promising strategy for mitigating the initiation and progression of neuropathological conditions.

Novel Insights into Parkin-Mediated Mitochondrial Dysfunction and "Mito-Inflammation" in α-Synuclein Toxicity. The Role of the cGAS-STING Signalling Pathway.

The prevalence of age-related neurodegenerative diseases, such as Parkinson's disease (PD) and related disorders continues to grow worldwide. Increasing evidence links intracellular inclusions of misfolded alpha-synuclein (α-syn) aggregates, so-called Lewy bodies (LB) and Lewy neuritis, to the progressive pathology of PD and other synucleinopathies. Our previous findings established that α-syn oligomers induce S-nitrosylation and deregulation of the E3-ubiquitin ligase Parkin, leading to mitochondrial disturbances in neuronal cells. The accumulation of damaged mitochondria as a consequence, together with the release of mitochondrial-derived damage-associated molecular patterns (mtDAMPs) could activate the innate immune response and induce neuroinflammation ("mito-inflammation"), eventually accelerating neurodegeneration. However, the molecular pathways that transmit pro-inflammatory signals from damaged mitochondria are not well understood. One of the proposed pathways could be the cyclic GMP-AMP synthase (cGAS) - stimulator of interferon genes (STING) (cGAS-STING) pathway, which plays a pivotal role in modulating the innate immune response. It has recently been suggested that cGAS-STING deregulation may contribute to the development of various pathological conditions. Especially, its excessive engagement may lead to neuroinflammation and appear to be essential for the development of neurodegenerative brain diseases, including PD. However, the precise molecular mechanisms underlying cGAS-STING pathway activation in PD and other synucleinopathies are not fully understood. This review focuses on linking mitochondrial dysfunction to neuroinflammation in these disorders, particularly emphasizing the role of the cGAS-STING signaling. We propose the cGAS-STING pathway as a critical driver of inflammation in α-syn-dependent neurodegeneration and hypothesize that cGAS-STING-driven "mito-inflammation" may be one of the key mechanisms promoting the neurodegeneration in PD. Understanding the molecular mechanisms of α-syn-induced cGAS-STING-associated "mito-inflammation" in PD and related synucleinopathies may contribute to the identification of new targets for the treatment of these disorders.

Bongkrekic acid alleviates airway inflammation via breaking the mPTP/mtDAMPs/RAGE feedback loop in a steroid-insensitive asthma model.

Mitochondrial dysfunction is critical in the pathogenesis of asthma. Mitochondrial permeability transition pore (mPTP) regulates the release of mitochondrial damage-associated molecular patterns (mtDAMPs) to maintain mitochondrial homeostasis. Bongkrekic acid (BKA) is a highly selective inhibitor of mPTP opening, participates the progression of various diseases. This research investigated the exact roles of BKA and mPTP in the pathogenesis of asthma and elucidated its underlying mechanisms. In the present study, cytochrome c, one of the mtDAMPs, levels were elevated in asthmatic patients, and associated to airway inflammation and airway obstruction. BKA, the inhibitor of mPTP markedly reversed TDI-induced airway hyperresponsiveness, airway inflammation, and mitochondrial dysfunction. Pretreatment with mitochondrial precipitation, to simulate the release of mtDAMPs, further increased TDI-induced airway inflammation and the expression of RAGE in mice. Administration of the inhibitor of RAGE, FPS-ZM1, alleviated the airway inflammation, the abnormal open of mPTP and mitochondrial dysfunction induced by mtDAMPs and TDI. Furthermore, stimulation with different mtDAMPs activated RAGE signaling in human bronchial epithelial cells. Accordingly, our study indicated that mPTP was important and BKA was efficient in alleviating inflammation in TDI-induced asthma. A positive feedback loop involving mPTP, mtDAMPs and RAGE was present in TDI-induced asthma, indicating that mPTP might serve as a potential therapeutic target for asthma.

The role of mtDAMPs in the trauma-induced systemic inflammatory response syndrome.

Systemic inflammatory response syndrome (SIRS) is a non-specific exaggerated defense response caused by infectious or non-infectious stressors such as trauma, burn, surgery, ischemia and reperfusion, and malignancy, which can eventually lead to an uncontrolled inflammatory response. In addition to the early mortality due to the "first hits" after trauma, the trauma-induced SIRS and multiple organ dysfunction syndrome (MODS) are the main reasons for the poor prognosis of trauma patients as "second hits". Unlike infection-induced SIRS caused by pathogen-associated molecular patterns (PAMPs), trauma-induced SIRS is mainly mediated by damage-associated molecular patterns (DAMPs) including mitochondrial DAMPs (mtDAMPs). MtDAMPs released after trauma-induced mitochondrial injury, including mitochondrial DNA (mtDNA) and mitochondrial formyl peptides (mtFPs), can activate inflammatory response through multiple inflammatory signaling pathways. This review summarizes the role and mechanism of mtDAMPs in the occurrence and development of trauma-induced SIRS.

Mitochondrial dysfunction and mitochondrion-targeted therapeutics in liver diseases.

The liver is a vital metabolic and detoxifying organ and suffers diverse endogenous or exogenous damage. Hepatocyte mitochondria experience various structural and functional defects from liver injury, bearing oxidative stress, metabolic dysregulation, and the disturbance of mitochondrial quality control (MQC) mechanisms. Mitochondrial malfunction initiates the mitochondria-mediated apoptotic pathways and the release of damage signals, aggravating liver damage and disease progression via inflammation and reparative fibrogenesis. Removal of mitochondrial impairment or the improvement of MQC mechanisms restore mitochondrial homeostasis and benefit liver health. This review discusses the association of mitochondrial disorders with hepatic pathophysiological processes and the resultant potential of mitochondrion-targeting therapeutics for hepatic disorders. The recent advances in the MQC mechanisms and the mitochondrial-derived damage-associated molecular patterns (DAMPs) in the pathology and treatment of liver disease are particularly focussed.

Altered lung metabolism and mitochondrial DAMPs in lung injury due to acute kidney injury.

Acute respiratory distress syndrome (ARDS) is a common cause of mortality in patients with acute kidney injury (AKI). Inflammatory crosstalk from the kidney to the lung has been shown to contribute to lung injury after AKI, but anti-inflammatory therapies have not been proven beneficial in human studies. Recently, AKI was shown to alter mitochondria and related metabolic pathways in the heart, but the impact of AKI on lung metabolism has not been investigated to our knowledge. In this study, we evaluated the metabolomic profile of the lung following renal ischemia and reperfusion to identify novel pathways that may be modifiable. We randomized C57BL/6 mice to 20 minutes of bilateral renal arterial clamping or sham operation under ketamine/xylazine anesthesia. At 4 hours after reperfusion, we found a significant increase in markers of lung injury, as well as significant metabolomic changes across lung, kidney, plasma and bronchoalveolar lavage fluid (BALF) compared to shams. Comparative analyses revealed that the fatty acid oxidation pathway was the most significantly altered metabolic pathway, a finding which is consistent with mitochondrial dysfunction systemically and in the lung. These metabolomic changes correlated with the extracellular accumulation of the mitochondrial damage associated molecular patterns (mtDAMPs), mitochondrial DNA (mtDNA) and transcription factor A, mitochondria (TFAM). Finally, we found that intraperitoneal injection of renal mtDAMPs caused metabolomic changes consistent with mitochondrial dysfunction in the lung in vivo. Mitochondrial function and mtDAMPs warrant further investigation as potential therapeutic targets in preventing lung injury because of AKI.

Mitophagy in hepatocytes: Types, initiators and role in adaptive ethanol metabolism☆.

Mitophagy (mitochondrial autophagy) in hepatocytes is an essential quality control mechanism that removes for lysosomal digestion damaged, effete and superfluous mitochondria. Mitophagy has distinct variants. In type 1 mitophagy, typical of nutrient deprivation, cup-shaped sequestration membranes (phagophores) grow, surround and sequester individual mitochondria into mitophagosomes, often in coordination with mitochondrial fission. After sequestration, the outer compartment of the mitophagosome acidifies and the entrapped mitochondrion depolarizes, followed by fusion with lysosomes. By contrast, mitochondrial depolarization stimulates type 2 mitophagy, which is characterized by coalescence of autophagic microtubule-associated protein 1A/1B-light chain 3 (LC3)-containing structures on mitochondrial surfaces without the formation of a phagophore or mitochondrial fission. Oppositely to type 1 mitophagy, the inhibition of phosphoinositide-3-kinase (PI3K) does not block type 2 mitophagy. In type 3 mitophagy, or micromitophagy, mitochondria-derived vesicles (MDVs) enriched in oxidized proteins bud off from mitochondrial inner and outer membranes and incorporate into multivesicular bodies by vesicle scission into the lumen. In response to ethanol feeding, widespread ethanol-induced hepatocellular mitochondrial depolarization occurs to facilitate hepatic ethanol metabolism. As a consequence, type 2 mitophagy develops in response to the mitochondrial depolarization. After chronic high ethanol feeding, processing of depolarized mitochondria by mitophagy becomes compromised, leading to release of mitochondrial damage-associated molecular patterns (mtDAMPs) that promote inflammatory and profibrogenic responses. We propose that the persistence of mitochondrial responses for acute ethanol metabolism links initial adaptive ethanol metabolism to mitophagy and then to chronic maladaptive changes initiating onset and the progression of alcoholic liver disease (ALD).