Defective Mitophagy Research Articles

PINK1/Parkin-mediated mitophagy in neurodegenerative diseases.

Mitochondria play key roles in bioenergetics, metabolism, and signaling; therefore, stable mitochondrial function is essential for cell survival, particularly in energy-intensive neuronal cells. In neurodegenerative diseases, damaged mitochondria accumulate in neurons causing associated bioenergetics deficiency, impaired cell signaling, defective cytoplasmic calcium buffering, and other pathological changes. Mitochondrial quality control is an important mechanism to ensure the maintenance of mitochondrial health, homeostasis, and mitophagy, the latter of which is a pathway that delivers defective mitochondria to the lysosome for degradation. Defective mitophagy is thought to be responsible for the accumulation of damaged mitochondria, which leads to cellular dysfunction and/or death in neurodegenerative diseases. PINK1/Parkin mainly regulates ubiquitin-dependent mitophagy, which is crucial for many aspects of mitochondrial physiology, particularly the initiation of autophagic mechanisms. Therefore, in the present review, we summarize the current knowledge of the conventional mitophagy pathway, focusing on the molecular mechanisms underlying mitophagy dysregulation in prion disease and other age-related neurodegenerative diseases, especially in relation to the PINK1/Parkin pathway. Moreover, we list the inducers of mitophagy that possess neuroprotective effects, in addition to their mechanisms related to the PINK1/Parkin pathway. These mechanisms may provide potential interventions centered on the regulation of mitophagy and offer therapeutic strategies for the treatment of neurodegenerative diseases.

The GET pathway serves to activate Atg32-mediated mitophagy by ER targeting of the Ppg1-Far complex.

Mitophagy removes defective or superfluous mitochondria via selective autophagy. In yeast, the pro-mitophagic protein Atg32 localizes to the mitochondrial surface and interacts with the scaffold protein Atg11 to promote degradation of mitochondria. Although Atg32-Atg11 interactions are thought to be stabilized by Atg32 phosphorylation, how this posttranslational modification is regulated remains obscure. Here, we show that cells lacking the guided entry of the tail-anchored protein (GET) pathway exhibit reduced Atg32 phosphorylation and Atg32-Atg11 interactions, which can be rescued by additional loss of the ER-resident Ppg1-Far complex, a multi-subunit phosphatase negatively acting in mitophagy. In GET-deficient cells, Ppg1-Far is predominantly localized to mitochondria. An artificial ER anchoring of Ppg1-Far in GET-deficient cells significantly ameliorates defects in Atg32-Atg11 interactions and mitophagy. Moreover, disruption of GET and Msp1, an AAA-ATPase that extracts non-mitochondrial proteins localized to the mitochondrial surface, elicits synthetic defects in mitophagy. Collectively, we propose that the GET pathway mediates ER targeting of Ppg1-Far, thereby preventing dysregulated suppression of mitophagy activation.

Mitochondrial Autophagy in Ischemic Aged Livers

Mitochondrial autophagy (mitophagy) is a central catabolic event for mitochondrial quality control. Defective or insufficient mitophagy, thus, can result in mitochondrial dysfunction, and ultimately cell death. There is a strong causal relationship between ischemia/reperfusion (I/R) injury and mitochondrial dysfunction following liver resection and transplantation. Compared to young patients, elderly patients poorly tolerate I/R injury. Accumulation of abnormal mitochondria after I/R is more prominent in aged livers than in young counterparts. This review highlights how altered autophagy is mechanistically involved in age-dependent hypersensitivity to reperfusion injury.

Altered PLD3 exonuclease activity impacts on lysosomal and mitochondrial homeostasis

AbstractBackgroundPhospholipase D3 (PLD3) is a single‐pass type II membrane protein that is majorly localized to late endosomes/lysosomes (LE/Lys) where it functions as a 5'‐3' exonuclease that degrades ssDNA. Whereas PLD3 has been identified as risk factor for late‐onset Alzheimer’s disease (LOAD), knockout studies have resulted in conflicting data regarding its impact on the amyloid precursor protein metabolism. Moreover, the substrates for PLD3 in LE/Lys remain unexploredMethodCRISPR/Cas9 gene editing was used to generate PLD3 knockout (KO) SH‐SY5Y cells that were subsequently stably rescued with wild‐type PLD3 and coding‐variants (M6R & V232M). All cell lines were evaluated for morphological and functional alterations of the LE/Lys compartment, including lipid profiling and analysis of the nucleotide content of LE/Lys magnetically isolated from the different cell lines. We optimized a PLD3 activity assay and analyzed the LE/Lys nucleotide content as a means to identify PLD3 substrates.ResultWe report that a PLD3 KO and LOAD‐associated risk variants lead to a significant lysosomal pathology, comprising an increase in the size of LE/Lys, more LAMP1 immunoreactivity, a reduced catabolic activity, an increased propensity for leakage and a marked increase in cholesterol content and in storage lipids. At the ultrastructural level, this is accompanied with the appearance of multilamellar bodies, sometimes including mitochondrial remnants. This is suggestive for a defective mitophagy, which we confirm on the light microscopy level using mKeima assays. Furthermore, we provide support for a role of PLD3 in the homeostatic degradation of mtDNA. We argue that when PLD3’s role is compromised, this leads to a build‐up of the lysosomal nucleotide content, impacting on the normal functioning of LE/Lys. We are currently analysing alterations in downstream cellular signaling pathways, including the TLR9 cascade.ConclusionCollectively, our findings subscribe a key role for PLD3 exonuclease activity in lysosomal homeostasis. Its dysfunction, as occurs in LOAD, leads to the co‐occurrence of lysosomal and mitochondrial defects.

Mitochondrial Dysfunction as an Underlying Cause of Skeletal Muscle Disorders.

Mitochondria are an important energy source in skeletal muscle. A main function of mitochondria is the generation of ATP for energy through oxidative phosphorylation (OXPHOS). Mitochondrial defects or abnormalities can lead to muscle disease or multisystem disease. Mitochondrial dysfunction can be caused by defective mitochondrial OXPHOS, mtDNA mutations, Ca2+ imbalances, mitochondrial-related proteins, mitochondrial chaperone proteins, and ultrastructural defects. In addition, an imbalance between mitochondrial fusion and fission, lysosomal dysfunction due to insufficient biosynthesis, and/or defects in mitophagy can result in mitochondrial damage. In this review, we explore the association between impaired mitochondrial function and skeletal muscle disorders. Furthermore, we emphasize the need for more research to determine the specific clinical benefits of mitochondrial therapy in the treatment of skeletal muscle disorders.

Dynamin-Related Protein 1 Is Involved in Mitochondrial Damage, Defective Mitophagy, and NLRP3 Inflammasome Activation Induced by MSU Crystals.

Excessive generation of reactive oxygen species (ROS) has great impacts on MSU crystal-induced inflammation. Drp1-dependent mitochondrial fission is closely associated with mitochondrial ROS levels. However, whether Drp1 signaling contributes to MSU crystal-induced inflammation remains unclear. Mice bone marrow-derived macrophages (BMDMs) were primed with LPS and then stimulated with MSU suspensions for 12 h. The protein levels associated with mitochondrial dynamics, oxidative stress, and mitophagy were detected by Western blot. BMDMs were loaded with MitoTracker Green probe to detect mitochondrial morphology. To measure mitochondrial reactive oxygen species (ROS) and total ROS levels, cells were loaded, respectively, with MitoSOX and DHE probes. The effects of Mito-TEMPO, an antioxidant that targets the mitochondria or DRP1 inhibitor (Mdivi-1) on MSU crystal-induced peritonitis and arthritis mouse models, were evaluated. Our study revealed that MSU crystal stimulation resulted in elevation of mitochondrial fragmentation of BMDMs. Treatment with Mito-TEMPO or Drp1 knockdown significantly ameliorated the mitochondrial damage induced by MSU crystals. BMDMs exposure to MSU crystals increased the expression of auto/mitophagy marker proteins and promoted the fusion of mitophagosomes with lysosomes, leading to accumulation of mitolysosomes. Drp1 knockdown alleviated defective mitophagy and activation of the NLRP3 inflammasome in MSU crystal-treated BMDMs. This study indicates that there is crosstalk between mitochondrial ROS and Drp1 signaling in MSU crystal-induced inflammation. Drp1 signaling is involved in MSU crystal-induced mitochondrial damage, impaired mitophagy and NLRP3 inflammasome activation.

The Absence of Parkin Does Not Promote Dopamine or Mitochondrial Dysfunction in PolgAD257A/D257A Mitochondrial Mutator Mice.

Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). In this study, we generated a transgenic model by crossing germline Parkin-/- mice with PolgAD257A mice, an established model of premature aging and mitochondrial stress. We hypothesized that loss of Parkin-/- in PolgAD257A/D257A mice would exacerbate mitochondrial dysfunction, leading to loss of dopamine neurons and nigral-striatal specific neurobehavioral motor dysfunction. We found that aged Parkin-/-/PolgAD257A/D257A male and female mice exhibited severe behavioral deficits, nonspecific to the nigral-striatal pathway, with neither dopaminergic neurodegeneration nor reductions in striatal dopamine. We saw no difference in expression levels of nuclear-encoded subunits of mitochondrial markers and mitochondrial Complex I and IV activities, although we did observe substantial reductions in mitochondrial-encoded COX41I, indicating mitochondrial dysfunction as a result of PolgAD257A/D257A mtDNA mutations. Expression levels of mitophagy markers LC3I/LC3II remained unchanged between cohorts, suggesting no overt mitophagy defects. Expression levels of the parkin substrates, VDAC, NLRP3, and AIMP2 remained unchanged, suggesting no parkin dysfunction. In summary, we were unable to observe dopaminergic neurodegeneration with corresponding nigral-striatal neurobehavioral deficits, nor Parkin or mitochondrial dysfunction in Parkin-/-/PolgAD257A/D257A mice. These findings support a lack of synergism of Parkin loss on mitochondrial dysfunction in mouse models of mitochondrial deficits.SIGNIFICANCE STATEMENT Producing a mouse model of Parkinson's disease (PD) that is etiologically relevant, recapitulates clinical hallmarks, and exhibits reproducible results is crucial to understanding the underlying pathology and in developing disease-modifying therapies. Here, we show that Parkin-/-/PolgAD257A/D257A mice, a previously reported PD mouse model, fails to reproduce a Parkinsonian phenotype. We show that these mice do not display dopaminergic neurodegeneration nor nigral-striatal-dependent motor deficits. Furthermore, we report that Parkin loss does not synergize with mitochondrial dysfunction. Our results demonstrate that Parkin-/-/PolgAD257A/D257A mice are not a reliable model for PD and adds to a growing body of work demonstrating that Parkin loss does not synergize with mitochondrial dysfunction in mouse models of mitochondrial deficits.

Treadmill Exercise Improves PINK1/Parkin-Mediated Mitophagy Activity Against Alzheimer's Disease Pathologies by Upregulated SIRT1-FOXO1/3 Axis in APP/PS1 Mice.

Although treadmill exercise is effective against Alzheimer's disease (AD), the molecular mechanisms underlying these effects are not fully understood. Recent literature has linked the accumulation of damaged mitochondria and defective mitophagy to AD progression. Here, we determined that abnormally activated PINK1/Parkin pathway-mediated mitophagy plays an important role in AD progression and pathogenesis in 6-month-old APP/PS1 mice. We used the lysosomal inhibitor chloroquine and demonstrated that a 12-week treadmill exercise program improved mitochondrial function, decreased accumulation of β-amyloid plaques, and ameliorated loss of learning and memory ability by enhancing PINK1/Parkin-mediated mitophagy activity in the hippocampus of APP/PS1 mice. Moreover, using the SIRT1 inhibitor EX527, we found that 12weeks of treadmill exercise rescued PINK1/Parkin-mediated mitophagy by activating the SIRT1-FOXO1/3 axis in the hippocampus of APP/PS1 mice. These findings reveal that activating PINK1/Parkin-mediated mitophagy is a promising strategy for AD treatment, and that the SIRT1-FOXO1/3 axis is a potential candidate for the development of mitophagy enhancers.

Defective PTEN-induced kinase 1/Parkin mediated mitophagy and neurodegenerative diseases.

The selective degradation of mitochondria through mitophagy is a crucial process for maintaining mitochondrial function and cellular health. Mitophagy is a specialized form of selective autophagy that uses unique machinery to recognize and target damaged mitochondria for mitophagosome- and lysosome-dependent degradation. This process is particularly important in cells with high metabolic activity like neurons, and the accumulation of defective mitochondria is a common feature among neurodegenerative disorders. Here, we describe essential steps involved in the induction and progression of mitophagy, and then highlight the various mechanisms that specifically contribute to defective mitophagy in highly prevalent neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and Amyotrophic Lateral Sclerosis.

Sestrin 2 Deficiency Exacerbates Noise-Induced Cochlear Injury Through Inhibiting ULK1/Parkin-Mediated Mitophagy.

Aims: Noise damage to auditory hair cells is associated with oxidative stress and mitochondrial dysfunction. This study aimed to investigate the possible effect of sestrin 2 (SESN2), an endogenous antioxidant protein, on noise-induced hearing loss (NIHL) and the underlying mechanisms. Results: We identified SESN2 as a protective factor against oxidative stress in NIHL through activation of Parkin-mediated mitophagy. Consistently, SESN2 expression was increased and mitophagy was induced during the early stage after a temporary threshold shift due to noise exposure or hydrogen peroxide(H2O2) stimulation; conversely, SESN2 deficiency blocked mitophagy and exacerbated acoustic trauma. Mechanistically, SESN2 interacted with Unc-51-like protein kinase 1(ULK1), promoting ULK1 protein-level stabilization by interfering with its proteasomal degradation. This stabilization is essential for mitophagy initiation, since restoring ULK1 expression in SESN2-silenced cells rescued mitophagy defects. Innovation and Conclusion: Our results provide novel insights regarding SESN2 as a therapeutic target against noise-induced cochlear injury, possibly through improved mitophagy. Antioxid. Redox Signal. 38, 115-136.

Targeting Deubiquitinating Enzymes (DUBs) That Regulate Mitophagy via Direct or Indirect Interaction with Parkin.

The quality control of mitochondria is critical for the survival of cells, and defects in the pathways required for this quality control can lead to severe disease. A key quality control mechanism in cells is mitophagy, which functions to remove damaged mitochondria under conditions of various stresses. Defective mitophagy can lead to a number of diseases including neurodegeneration. It has been proposed that an enhancement of mitophagy can improve cell survival, enhance neuronal function in neurodegeneration and extend health and lifespans. In this review, we highlight the role of deubiquitinating enzymes (DUBs) in the regulation of mitophagy. We summarise the current knowledge on DUBs that regulate mitophagy as drug targets and provide a list of small molecule inhibitors that are valuable tools for the further development of therapeutic strategies targeting the mitophagy pathway in neurodegeneration.

Activation of β2-adrenergic Receptor Ameliorates Amyloid-β-induced Mitophagy Defects and Tau Pathology in Mice

Defective mitophagy and mitochondrial dysfunction have been linked to aging and Alzheimer’s disease (AD). β2-Adrenergic receptor (ADRB2) is critical for mitochondrial and cognitive function. However, researchers have not clearly determined whether ADRB2 activation ameliorates defective mitophagy and cognitive deficits in individuals with AD. Here, we observed that the activation of ADRB2 by clenbuterol (Clen, ADRB2 agonist, 2 mg/kg/day) ameliorated amyloid-β-induced (Aβ1-42 bilateral intracerebral infusion, 2 μl, 5 μg/μl) memory deficits. Activation of ADRB2 also attenuated Aβ-induced mitochondrial dysfunction, as revealed by increased ATP levels, mitochondrial membrane potential (MMP/Δψm) and complex I activity. Further studies revealed that ADRB2 activation restored mitophagy deficits, as revealed by the increased light chain 3 (LC3)-II/LC3-I ratio, Atg5 levels, and Atg7 levels and decreased p62 levels, along with the upregulation of PTEN-induced putative kinase 1 (PINK1), Parkin and NAD+ levels. Activation of ADRB2 rescued Aβ-induced oxidative stress and neuronal death. ADRB2 activation also attenuated Aβ-induced tau hyperphosphorylation by regulating glycogen synthase kinase-3β expression in the hippocampus. Finally, we established that Clen improved mitophagy and attenuated mitochondrial dysfunction, and tau pathology in mice by activating the ADRB2/Akt/PINK1 signaling pathway. Conversely, the inhibition of ADRB2 by propranolol (βAR antagonist, 10 μM) blocked the Clen-mediated improvements in pathological changes in N2a cells. The results from the present study indicate that ADRB2 activation may be a therapeutic strategy for AD.

A new beta cell-specific mitophagy reporter mouse shows that metabolic stress leads to accumulation of dysfunctional mitochondria despite increased mitophagy.

Mitophagy, the selective autophagy of mitochondria, is essential for maintenance of mitochondrial function. Recent studies suggested that defective mitophagy in beta cells caused diabetes. However, because of technical difficulties, the development of a convenient and reliable method to evaluate mitophagy in beta cells in vivo is needed. The aim of this study was to establish beta cell-specific mitophagy reporter mice and elucidate the role of mitophagy in beta cell function under metabolically stressed conditions induced by a high-fat diet (HFD). Mitophagy was assessed using newly generated conditional mitochondrial matrix targeting mitophagy reporter (CMMR) mice, in which mitophagy can be visualised specifically in beta cells in vivo using a fluorescent probe sensitive to lysosomal pH and degradation. Metabolic stress was induced in mice by exposure to the HFD for 20 weeks. The accumulation of dysfunctional mitochondria was examined by staining for functional/total mitochondria and reactive oxygen species (ROS) using specific fluorescent dyes and antibodies. To investigate the molecular mechanism underlying mitophagy in beta cells, overexpression and knockdown experiments were performed. HFD-fed mice were examined to determine whether chronic insulin treatment for 6 weeks could ameliorate mitophagy, mitochondrial function and impaired insulin secretion. Exposure to the HFD increased the number of enlarged (HFD-G) islets with markedly elevated mitophagy. Mechanistically, HFD feeding induced severe hypoxia in HFD-G islets, which upregulated mitophagy through the hypoxia-inducible factor 1-ɑ (Hif-1ɑ)/BCL2 interacting protein 3 (BNIP3) axis in beta cells. However, HFD-G islets unexpectedly showed the accumulation of dysfunctional mitochondria due to excessive ROS production, suggesting an insufficient capacity of mitophagy for the degradation of dysfunctional mitochondria. Chronic administration of insulin ameliorated hypoxia and reduced ROS production and dysfunctional mitochondria, leading to decreased mitophagy and restored insulin secretion. We demonstrated that CMMR mice enabled the evaluation of mitophagy in beta cells. Our results suggested that metabolic stress induced by the HFD caused the aberrant accumulation of dysfunctional mitochondria, which overwhelmed the mitophagic capacity and was associated with defective maintenance of mitochondrial function and impaired insulin secretion.

Drug Discovery Strategies for Inherited Retinal Degenerations.

Simple SummaryInherited retinal degeneration is a group of heterogeneous genetic disorders impairing vision. In these diseases, photoreceptor or retinal ganglion cells become dysfunctional and degenerate. Currently, no cures exist for these devastating blinding conditions. In this review, we will discuss targets and drug discovery strategies for inherited retinal degeneration using animal models, stem cells, and small molecule screening with updates on preclinical developments.Inherited retinal degeneration is a group of blinding disorders afflicting more than 1 in 4000 worldwide. These disorders frequently cause the death of photoreceptor cells or retinal ganglion cells. In a subset of these disorders, photoreceptor cell death is a secondary consequence of retinal pigment epithelial cell dysfunction or degeneration. This manuscript reviews current efforts in identifying targets and developing small molecule-based therapies for these devastating neuronal degenerations, for which no cures exist. Photoreceptors and retinal ganglion cells are metabolically demanding owing to their unique structures and functional properties. Modulations of metabolic pathways, which are disrupted in most inherited retinal degenerations, serve as promising therapeutic strategies. In monogenic disorders, great insights were previously obtained regarding targets associated with the defective pathways, including phototransduction, visual cycle, and mitophagy. In addition to these target-based drug discoveries, we will discuss how phenotypic screening can be harnessed to discover beneficial molecules without prior knowledge of their mechanisms of action. Because of major anatomical and biological differences, it has frequently been challenging to model human inherited retinal degeneration conditions using small animals such as rodents. Recent advances in stem cell-based techniques are opening new avenues to obtain pure populations of human retinal ganglion cells and retinal organoids with photoreceptor cells. We will discuss concurrent ideas of utilizing stem-cell-based disease models for drug discovery and preclinical development.

422.4: Defective Mitophagy in Aged Macrophages Promotes Mitochondrial DNA Cytosolic Leakage to Activate STING Signaling During Liver Ischemia and Reperfusion Injury

422.4: Defective Mitophagy in Aged Macrophages Promotes Mitochondrial DNA Cytosolic Leakage to Activate STING Signaling During Liver Ischemia and Reperfusion Injury

DJ-1 is an essential downstream mediator in PINK1/parkin-dependent mitophagy.

Loss-of-function mutations in the PRKN, PINK1 and PARK7 genes (encoding parkin, PINK1 and DJ-1, respectively) cause autosomal recessive forms of Parkinson's disease. PINK1 and parkin jointly mediate selective autophagy of damaged mitochondria (mitophagy), but the mechanisms by which loss of DJ-1 induces Parkinson's disease are not well understood. Here, we investigated PINK1/parkin-mediated mitophagy in cultured human fibroblasts and induced pluripotent stem cell-derived neurons with homozygous PARK7 mutations. We found that DJ-1 is essential for PINK1/parkin-mediated mitophagy. Loss of DJ-1 did not interfere with PINK1 or parkin activation after mitochondrial depolarization but blocked mitophagy further downstream by inhibiting recruitment of the selective autophagy receptor optineurin to depolarized mitochondria. By contrast, starvation-induced, non-selective autophagy was not affected by loss of DJ-1. In wild-type fibroblasts and induced pluripotent stem cell-derived dopaminergic neurons, endogenous DJ-1 translocated to depolarized mitochondria in close proximity to optineurin. DJ-1 translocation to depolarized mitochondria was dependent on PINK1 and parkin and did not require oxidation of cysteine residue 106 of DJ-1. Overexpression of DJ-1 did not rescue the mitophagy defect of PINK1- or parkin-deficient cells. These findings position DJ-1 downstream of PINK1 and parkin in the same pathway and suggest that disruption of PINK1/parkin/DJ-1-mediated mitophagy is a common pathogenic mechanism in autosomal recessive Parkinson's disease.

Roles of microglial mitophagy in neurological disorders.

Microglia are the resident innate immune cells in the central nervous system (CNS) that serve as the first line innate immunity in response to pathogen invasion, ischemia and other pathological stimuli. Once activated, they rapidly release a variety of inflammatory cytokines and phagocytose pathogens or cell debris (termed neuroinflammation), which is beneficial for maintaining brain homeostasis if appropriately activated. However, excessive or uncontrolled neuroinflammation may damage neurons and exacerbate the pathologies in neurological disorders. Microglia are highly dynamic cells, dependent on energy supply from mitochondria. Moreover, dysfunctional mitochondria can serve as a signaling platform to facilitate innate immune responses in microglia. Mitophagy is a means of clearing damaged or redundant mitochondria, playing a critical role in the quality control of mitochondrial homeostasis and turnover. Mounting evidence has shown that mitophagy not only limits the inflammatory response in microglia but also affects their phagocytosis, whereas mitochondria dysfunction and mitophagy defects are associated with aging and neurological disorders. Therefore, targeting microglial mitophagy is a promising therapeutic strategy for neurological disorders. This article reviews and highlights the role and regulation of mitophagy in microglia in neurological conditions, and the research progress in manipulating microglial mitophagy and future directions in this field are also discussed.

The presence of MTDNA mutations in THP1-based cybrid cells affects the efficiently of FCCP-induced mitophagy

Background and Aims : Mitophagy is an effective way to clearance of dysfunctional mitochondria. A disturbance in the clearance of dysfunctional organelles and their accumulation may indicate that mitophagy is defective. We hypothesize that mtDNA mutations may cause defective mitophagy.

Mitochondrial impairment and repair in the pathogenesis of systemic lupus erythematosus.

Nucleic acid autoantibodies, increase type I interferon (IFN-α) levels, and immune cell hyperactivation are hallmarks of systemic lupus erythematosus (SLE). Notably, immune cell activation requires high level of cellular energy that is predominately generated by the mitochondria. Mitochondrial reactive oxygen species (mROS), the byproduct of mitochondrial energy generation, serves as an essential mediator to control the activation and differentiation of cells and regulate the antigenicity of oxidized nucleoids within the mitochondria. Recently, clinical trials on normalization of mitochondrial redox imbalance by mROS scavengers and those investigating the recovery of defective mitophagy have provided novel insights into SLE prophylaxis and therapy. However, the precise mechanism underlying the role of oxidative stress-related mitochondrial molecules in skewing the cell fate at the molecular level remains unclear. This review outlines distinctive mitochondrial functions and pathways that are involved in immune responses and systematically delineates how mitochondrial dysfunction contributes to SLE pathogenesis. In addition, we provide a comprehensive overview of damaged mitochondrial function and impaired metabolic pathways in adaptive and innate immune cells and lupus-induced organ tissues. Furthermore, we summarize the potential of current mitochondria-targeting drugs for SLE treatment. Developing novel therapeutic approaches to regulate mitochondrial oxidative stress is a promising endeavor in the search for effective treatments for systemic autoimmune diseases, particularly SLE.

The intestinal microbial metabolite nicotinamide n-oxide prevents herpes simplex encephalitis via activating mitophagy in microglia

ABSTRACT Herpes simplex encephalitis (HSE), a complication of herpes simplex virus type I (HSV-1) infection causes neurological disorder or even death in immunocompromised adults and newborns. However, the intrinsic factors controlling the HSE outcome remain unclear. Here, we show that HSE mice exhibit gut microbiota dysbiosis and altered metabolite configuration and tryptophan-nicotinamide metabolism. HSV-1 neurotropic infection activated microglia, with changed immune properties and cell numbers, to stimulate antiviral immune response and contribute substantially to HSE. In addition, depletion of gut microbiota by oral antibiotics (ABX)-treatment triggered the hyper-activation of microglia, which in turn enhanced inflammatory immune response, and cytokine production, resulting in aggregated viral burden and HSE pathology. Furthermore, exogenous administration of nicotinamide n-oxide (NAMO), an oxidative product of nicotinamide derived from gut microbiota, to ABX-treated or untreated HSE mice significantly diminished microglia-mediated proinflammatory response and limited HSV-1 infection in CNS. Mechanistic study revealed that HSV-1 activates microglia by increasing mitochondrial damage via defective mitophagy, whereas microbial metabolite NAMO restores NAD+-dependent mitophagy to inhibit microglia activation and HSE progression. NAMO also prevented neuronal cell death triggered by HSV-1 infection or microglia-mediated microenvironmental toxicity. Finally, we show that NAMO is mainly generated by neomycin-sensitive bacteria, especially Lactobacillus_gasseri and Lactobacillus_reuteri. Together, these data demonstrate that gut microbial metabolites act as intrinsic restrictive factors against HSE progression via regulating mitophagy in microglia, implying further exploration of bacterial or nutritional approaches for treating neurotropic virus-related neurodegenerative diseases.