Changes In Mitochondrial Dynamics Research Articles

Sirt3-Mediated Opa1 Deacetylation Protects Against Sepsis-Induced Acute Lung Injury by Inhibiting Alveolar Macrophage Pro-Inflammatory Polarization.

Aims: Mitochondrial dynamics in alveolar macrophages (AMs) are associated with sepsis-induced acute lung injury (ALI). In this study, we aimed to investigate whether changes in mitochondrial dynamics could alter the polarization of AMs in sepsis-induced ALI and to explore the regulatory mechanism of mitochondrial dynamics by focusing on sirtuin (SIRT)3-induced optic atrophy protein 1 (OPA1) deacetylation. Results: The AMs of sepsis-induced ALI showed imbalanced mitochondrial dynamics and polarization to the M1 macrophage phenotype. In sepsis, SIRT3 overexpression promotes mitochondrial dynamic equilibrium in AMs. However, 3-(1H-1, 2, 3-triazol-4-yl) pyridine (3TYP)-specific inhibition of SIRT3 increased the mitochondrial dynamic imbalance and pro-inflammatory polarization of AMs and further aggravated sepsis-induced ALI. OPA1 is directly bound to and deacetylated by SIRT3 in AMs. In AMs of sepsis-induced ALI, SIRT3 protein expression was decreased and OPA1 acetylation was increased. OPA1 acetylation at the lysine 792 amino acid residue (OPA1-K792) promotes self-cleavage and is associated with an imbalance in mitochondrial dynamics. However, decreased acetylation of OPA1-K792 reversed the pro-inflammatory polarization of AMs and protected the barrier function of alveolar epithelial cells in sepsis-induced ALI. Innovation: Our study revealed, for the first time, the regulation of mitochondrial dynamics and AM polarization by SIRT3-mediated deacetylation of OPA1 in sepsis-induced ALI, which may serve as an intervention target for precision therapy of the disease. Conclusions: Our data suggest that imbalanced mitochondrial dynamics promote pro-inflammatory polarization of AMs in sepsis-induced ALI and that deacetylation of OPA1 mediated by SIRT3 improves mitochondrial dynamic equilibrium, thereby ameliorating lung injury.

Lineage-specific changes in mitochondrial properties during neural stem cell differentiation.

Neural stem cells (NSCs) reside in discrete regions of the adult mammalian brain where they can differentiate into neurons, astrocytes, and oligodendrocytes. Several studies suggest that mitochondria have a major role in regulating NSC fate. Here, we evaluated mitochondrial properties throughout NSC differentiation and in lineage-specific cells. For this, we used the neurosphere assay model to isolate, expand, and differentiate mouse subventricular zone postnatal NSCs. We found that the levels of proteins involved in mitochondrial fusion (Mitofusin [Mfn] 1 and Mfn 2) increased, whereas proteins involved in fission (dynamin-related protein 1 [DRP1]) decreased along differentiation. Importantly, changes in mitochondrial dynamics correlated with distinct patterns of mitochondrial morphology in each lineage. Particularly, we found that the number of branched and unbranched mitochondria increased during astroglial and neuronal differentiation, whereas the area occupied by mitochondrial structures significantly reduced with oligodendrocyte maturation. In addition, comparing the three lineages, neurons revealed to be the most energetically flexible, whereas astrocytes presented the highest ATP content. Our work identified putative mitochondrial targets to enhance lineage-directed differentiation of mouse subventricular zone-derived NSCs.

The Effect of Cold-Water Swimming on Energy Metabolism, Dynamics, and Mitochondrial Biogenesis in the Muscles of Aging Rats.

Our study aimed to explore the potential positive effects of cold water exercise on mitochondrial biogenesis and muscle energy metabolism in aging rats. The study involved 32 male and 32 female rats aged 15 months, randomly assigned to control sedentary animals, animals training in cold water at 5 ± 2 °C, or animals training in water at thermal comfort temperature (36 ± 2 °C). The rats underwent swimming training for nine weeks, gradually increasing the duration of the sessions from 2 min to 4 min per day, five days a week. The results demonstrated that swimming in thermally comfortable water improved the energy metabolism of aging rat muscles (increased metabolic rates expressed as increased ATP, ADP concentration, TAN (total adenine nucleotide) and AEC (adenylate energy charge value)) and increased mRNA and protein expression of fusion regulatory proteins. Similarly, cold-water swimming improved muscle energy metabolism in aging rats, as shown by an increase in muscle energy metabolites and enhanced mitochondrial biogenesis and dynamics. It can be concluded that the additive effect of daily activity in cold water influenced both an increase in the rate of energy metabolism in the muscles of the studied animals and an intensification of mitochondrial biogenesis and dynamics (related to fusion and fragmentation processes). Daily activity in warm water also resulted in an increase in the rate of energy metabolism in muscles, but at the same time did not cause significant changes in mitochondrial dynamics.

Biomarkers for prediction of CAR T therapy outcomes: current and future perspectives.

Chimeric antigen receptor (CAR) T cell therapy holds enormous potential for the treatment of hematologic malignancies. Despite its benefits, it is still used as a second line of therapy, mainly because of its severe side effects and patient unresponsiveness. Numerous researchers worldwide have attempted to identify effective predictive biomarkers for early prediction of treatment outcomes and adverse effects in CAR T cell therapy, albeit so far only with limited success. This review provides a comprehensive overview of the current state of predictive biomarkers. Although existing predictive metrics correlate to some extent with treatment outcomes, they fail to encapsulate the complexity of the immune system dynamics. The aim of this review is to identify six major groups of predictive biomarkers and propose their use in developing improved and efficient prediction models. These groups include changes in mitochondrial dynamics, endothelial activation, central nervous system impairment, immune system markers, extracellular vesicles, and the inhibitory tumor microenvironment. A comprehensive understanding of the multiple factors that influence therapeutic efficacy has the potential to significantly improve the course of CAR T cell therapy and patient care, thereby making this advanced immunotherapy more appealing and the course of therapy more convenient and favorable for patients.

Effect of CB1 Receptor Deficiency on Mitochondrial Quality Control Pathways in Gastrocnemius Muscle.

This study aims to explore the complex role of cannabinoid type 1 receptor (CB1) signaling in the gastrocnemius muscle, assessing physiological processes in both CB1+/+ and CB1-/- mice. The primary focus is to enhance our understanding of how CB1 contributes to mitochondrial homeostasis. At the tissue level, CB1-/- mice exhibit a substantial miRNA-related alteration in muscle fiber composition, characterized by an enrichment of oxidative fibers. CB1 absence induces a significant increase in the oxidative capacity of muscle, supported by elevated in-gel activity of Complex I and Complex IV of the mitochondrial respiratory chain. The increased oxidative capacity is associated with elevated oxidative stress and impaired antioxidant defense systems. Analysis of mitochondrial biogenesis markers indicates an enhanced capacity for new mitochondria production in CB1-/- mice, possibly adapting to altered muscle fiber composition. Changes in mitochondrial dynamics, mitophagy response, and unfolded protein response (UPR) pathways reveal a dynamic interplay in response to CB1 absence. The interconnected mitochondrial network, influenced by increased fusion and mitochondrial UPR components, underlines the dual role of CB1 in regulating both protein quality control and the generation of new mitochondria. These findings deepen our comprehension of the CB1 impact on muscle physiology, oxidative stress, and MQC processes, highlighting cellular adaptability to CB1-/-. This study paves the way for further exploration of intricate signaling cascades and cross-talk between cellular compartments in the context of CB1 and mitochondrial homeostasis.

Tumor Necrosis Factor-α Receptor 1 Mediates Borna Disease Virus 1-Induced Changes in Peroxisomal and Mitochondrial Dynamics in Neurons.

Borna disease virus 1 (BoDV1) causes a persistent infection in the mammalian brain. Peroxisomes and mitochondria play essential roles in the cellular antiviral immune response, but the effect of BoDV1 infection on peroxisomal and mitochondrial dynamics and their respective antioxidant capacities is still not clear. Using different mouse lines-i.e., tumor necrosis factor-α transgenic (TNFTg; to pro-inflammatory status), TNF receptor-1 knockout (TNFR1ko), and TNFR2ko mice in comparison to wild-type (Wt) mice-we analyzed the abundances of both organelles and their main antioxidant enzymes, catalase and superoxide dismutase 2 (SOD2), in neurons of the hippocampal, cerebral, and cerebellar cortices. In TNFTg mice, a strong increase in mitochondrial (6.9-fold) and SOD2 (12.1-fold) abundances was detected; meanwhile, peroxisomal abundance increased slightly (1.5-fold), but that of catalase decreased (2.9-fold). After BoDV1 infection, a strong decrease in mitochondrial (2.1-6.5-fold), SOD2 (2.7-9.1-fold), and catalase (2.7-10.3-fold) abundances, but a slight increase in peroxisomes (1.3-1.6-fold), were detected in Wt and TNFR2ko mice, whereas no changes occurred in TNFR1ko mice. Our data suggest that the TNF system plays a crucial role in the biogenesis of both subcellular organelles. Moreover, TNFR1 signaling mediated the changes in peroxisomal and mitochondrial dynamics after BoDV1 infection, highlighting new mechanisms by which BoDV1 may achieve immune evasion and viral persistence.

PDCD4 knockdown ameliorates lipopolysaccharide-induced endothelial cell damage by improving mitochondrial dynamics

To elucidate the role of programmed cell death factor 4 (PDCD4) in mitochondrial dysfunction caused by sepsis-related vascular endothelial damage. Cultured human umbilical vein endothelial cells (HUVECs) and mouse vascular endothelial cells (C166 cells) were transfected with a small interfering RNA targeting PDCD4 followed by treatment with lipopolysaccharide (LPS) alone or in combination with carbonyl cyanide 3-chlorophenylhydrazone (FCCP). The proteomic changes in the cells after PDCD4 knockdown were analyzed using LC-MS/MS technique. The mRNA expressions of PDCD4 and the genes associated with cell inflammation and apoptosis were detected with RT-PCR, and the expressions of FIS1, DRP1 and OPA1 proteins key to mitochondrial fission and fusion were determined using Western blotting. JC-1 and MitoSOX fluorescent probes were used to observe the changes in mitochondrial membrane potential and mitochondrial reactive oxygen species levels under by a laser confocal microscope. LPS stimulation of the cells significantly increased the mRNA expressions of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein 1 (MCP1) and enhanced the cellular expression of PDCD4 (P < 0.05). Proteomic analysis suggested a correlation between PDCD4 knockdown and changes in mitochondrial dynamics in the cells. LPS treatment significantly increased the expressions of mitochondrial fission proteins FIS1 and DRP1 and lowered the expression of the fusion protein OPA1 in the cells (P < 0.05), causing also mitochondrial oxidative stress and reduction of the mitochondrial membrane potential (P < 0.05). In HUVECs, treatment with FCCP significantly attenuated the protective effect of PDCD4 knockdown, which inhibited LPS-induced inflammation and oxidative stress and restored the balance between mitochondrial fission and fusion. PDCD4 knockdown protects vascular endothelial cells against LPS-induced damages by repressing mitochondrial fission and oxidative stress, promoting mitochondrial fusion, and maintaining normal mitochondrial function.

Mechanical Stretch-Induced ATP Release from Osteocytes Promotes Osteogenesis of Bone Marrow Mesenchymal Stem Cells.

Mandibular distraction osteogenesis (MDO) is a highly effective method for bone regeneration, commonly employed in treating craniofacial defects and deformities. Osteocytes sense mechanical forces in the pericellular space, relay external stimuli to biochemical changes, and send signals to other effector cells, including bone marrow mesenchymal stem cells (BM-MSCs), to regulate bone resorption and formation. Piezo1 potentially affects the secretion signal molecules of bone cells under mechanical stretch. The primary aim of this study was to enhance our comprehension of the molecular biology underlying this therapeutic approach and to identify specific signaling molecules that facilitate bone formation in response to stretch forces. Mechanical stretching was applied to negative controls and Piezo1 knockdown osteocyte-like MLO-Y4 cells. Alkaline phosphatase and Alizarin Red S staining were used to survey the osteogenic potential of BM-MSCs. The production and secretion content of adenosine triphosphate (ATP) was measured using ATP content determination analysis. Pathway-related and osteo-specific genes and proteins were evaluated using real-time polymerase chain reaction (RT-PCR), Western blots, and immunofluorescence. Mitochondrial organization was examined with a transmission electron microscope. The conditioned medium of stretch-exposed MLO-Y4s significantly upregulated osteogenesis-related indicators of BM-MSCs (p < 0.001). The upregulation of BM-MSC osteogenesis was associated with ATP release from osteocytes. Mechanically induced calcium transfer and transcriptional coactivator with PDZ-binding motif (TAZ) nuclear translocation mediated by Piezo1 could promote mitochondrial fission and ATP release. Osteocytes detected stretch forces through Piezo1, triggering calcium influx, TAZ nuclear translocation, and ATP production. The stretch stimulation of Piezo1 induces calcium influx, which in turn promotes calcium-related TAZ nuclear translocation, changes in mitochondrial dynamics, and the release of ATP in osteocytes. This signaling cascade leads to an up-regulation in the osteogenic capacity of BM-MSCs. Mitochondrial energy metabolism of mechanosensitive protein Piezo1-dependent and ATP release may provide a new effective intervention method for mechanically related bone remodeling.

Changes of mitochondrial dynamics during the progression of non-alcoholic fatty liver disease: a review

Changes of mitochondrial dynamics during the progression of non-alcoholic fatty liver disease: a review

Mitochondrial Dyshomeostasis as an Early Hallmark and a Therapeutic Target in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal multisystem disease characterized by progressive death of motor neurons, loss of muscle mass, and impaired energy metabolism. More than 40 genes are now known to be associated with ALS, which together account for the majority of familial forms of ALS and only 10% of sporadic ALS cases. To date, there is no consensus on the pathogenesis of ALS, which makes it difficult to develop effective therapy. Accumulating evidence indicates that mitochondria, which play an important role in cellular homeostasis, are the earliest targets in ALS, and abnormalities in their structure and functions contribute to the development of bioenergetic stress and disease progression. Mitochondria are known to be highly dynamic organelles, and their stability is maintained through a number of key regulatory pathways. Mitochondrial homeostasis is dynamically regulated via mitochondrial biogenesis, clearance, fission/fusion, and trafficking; however, the processes providing “quality control” and distribution of the organelles are prone to dysregulation in ALS. Here, we systematically summarized changes in mitochondrial turnover, dynamics, calcium homeostasis, and alterations in mitochondrial transport and functions to provide in-depth insights into disease progression pathways, which may have a significant impact on current symptomatic therapies and personalized treatment programs for patients with ALS.

Disrupted brain mitochondrial morphology after in vivo hydrogen sulfide exposure

Changes in mitochondrial dynamics are often associated with dietary patterns, medical treatments, xenobiotics, and diseases. Toxic exposures to hydrogen sulfide (H2S) harm mitochondria by inhibiting Complex IV and via other mechanisms. However, changes in mitochondrial dynamics, including morphology following acute exposure to H2S, are not yet fully understood. This study followed mitochondrial morphology changes over time after a single acute LCt50 dose of H2S by examining electron microscopy thalami images of surviving mice. Our findings revealed that within the initial 48 h after H2S exposure, mitochondrial morphology was impaired by H2S, supported by the disruption and scarcity of the cristae, which are required to enhance the surface area for ATP production. At the 72-h mark point, a spectrum of morphological cellular changes was observed, and the disordered mitochondrial network, accompanied by the probable disruption of mitophagy, was tied to changes in mitochondrial shape. In summary, this study sheds light on how acute exposure to high levels of H2S triggers alterations in mitochondrial shape and structure as early as 24 h that become more evident at 72 h post-exposure. These findings underscore the impact of H2S on mitochondrial function and overall cellular health.

The effect of exercise preconditioning with high-intensity interval training on cardiac protection following induction of myocardial infarction through mitochondrial dynamic changes in cardiac tissue in male rats

Exercise training prevents the adverse effects of Myocardial Infarction (MI) and Ischemia/Reperfusion (I / R) and it seems that mitochondria have an important role in exercise-induced cardioprotection. So, the purpose of this study was to investigate the effects of exercise preconditioning with 4 weeks of High-Intensity Exercise Training (HIIT) on cardiac damage and mitochondrial dynamic proteins as effective factors in cardiac protection following MI. Twenty Male Wistar rats were randomly divided into 4 groups HIIT + MI, MI, HIIT, and Control. Training groups performed 4 weeks (5 days per week) of high-intensity interval training. HIIT protocol consisted of 10*1min running intervals that were separated by 2 min rest. Training intensity varied every week. For induction of myocardial infarction, a subcutaneous injection of isoproterenol was used. Creatine Kinase (CK) and lactate Dehydrogenase (LDH) were measured in serum and Drp1, and Mfn2 gene expression were measured by the real-time PCR method in the heart tissue. The results of the present study showed that CK and LDH in MI were significantly higher in HIIT + MI (p &lt; 0.05). myocardial infarction results in a significant increase in Drp1 gene expression in the MI and HIIT + MI groups relative to the Control group. The expression of the Drp1 gene was lower in the HIIT + MI group than in the MI group, but it was not statistically significant. Also, the results demonstrated that Mfn2 was no significant difference between the groups (p &gt; 0.05). It seems that four weeks of exercise preconditioning with HIIT training reduced injury and necrosis in cardiac tissue and can increase cardio-protection. Also, no significant effect was observed in reducing Drp1 expression due to HIIT which may indicate the need for a longer training period.

Effect of exercise on improving myocardial mitochondrial function in decreasing diabetic cardiomyopathy.

Diabetic cardiomyopathy (DCM) is a significant cause of heart failure in patients with diabetes, and its pathogenesis is closely related to myocardial mitochondrial injury and functional disability. Studies have shown that the development of diabetic cardiomyopathy is related to disorders in mitochondrial metabolic substrates, changes in mitochondrial dynamics, an imbalance in mitochondrial Ca2+ regulation, defects in the regulation of microRNAs, and mitochondrial oxidative stress. Physical activity may play a role in resistance to the development of diabetic cardiomyopathy by improving myocardial mitochondrial biogenesis, the level of autophagy and dynamic changes in fusion and division; enhancing the ability to cope with oxidative stress; and optimising the metabolic substrates of the myocardium. This paper puts forward a new idea for further understanding the specific mitochondrial mechanism of the occurrence and development of diabetic cardiomyopathy and clarifying the role of exercise-mediated myocardial mitochondrial changes in the prevention and treatment of diabetic cardiomyopathy. This is expected to provide a new theoretical basis for exercise to reduce diabetic cardiomyopathy symptoms.

STAT3 modulates CD4+ T mitochondrial dynamics and function in aging.

Aging promotes numerous intracellular changes in T cells that impact their effector function. Our data show that aging promotes an increase in the localization of STAT3 to the mitochondria (mitoSTAT3), which promotes changes in mitochondrial dynamics and function and T-cell cytokine production. Mechanistically, mitoSTAT3 increased the activity of aging T-cell mitochondria by increasing complex II. Limiting mitoSTAT3 using a mitochondria-targeted STAT3 inhibitor, Mtcur-1 lowered complex II activity, prevented age-induced changes in mitochondrial dynamics and function, and reduced Th17 inflammation. Exogenous expression of a constitutively phosphorylated form of STAT3 in T cells from young adults mimicked changes in mitochondrial dynamics and function in T cells from older adults and partially recapitulated aging-related cytokine profiles. Our data show the mechanistic link among mitoSTAT3, mitochondrial dynamics, function, and T-cell cytokine production.

SAT429 Progesterone Secretion And The Estrous Cycle In The Mouse Are Disrupted By Mitochondrial Fusion Promoter M1 Injection During Proestrus

Abstract Disclosure: Y.P. Budi: None. M. Hsu: None. Y. Lin: None. Y. Lee: None. H. Chiu: None. C. Chiu: None. Y. Jiang: None. In the female reproductive system, mitochondria play a crucial role in steroid hormone synthesis. Literature reports on changes in mitochondrial dynamics throughout the ovarian cycle, but its role in the ovarian cycle is still unknown. In this study, a mitochondrial fusion promotor, M1, was used to study the impact of mitochondrial dynamics in the female reproductive system. The estrus cycle of mice was monitored before, during, and after the M1 treatment to test the impact of M1 on ovarian functions. Our results showed that M1 treatment in mice leads to the disruptions of estrous cycles in vagina smears. To observe the acute effects of M1, serum hormones level was observed, and the decrease in serum LH and progesterone was recorded in the animal. Similarly, our ovarian tissue culture also indicates inhibitions of progesterone secretion and ovulations. Although no significant changes in mitochondrial networks were observed in the ovaries, there was significant up-regulation of mitochondrial respiratory complexes in M1 treatments through transcriptomic analysis. In contrast to the estrogen and steroid biosynthesis up-regulated in M1, the extracellular matrix molecules, remodeling enzymes, and adhesion signaling decreased. Collectively, our study provides novel targets to regulate the ovarian cycles through the mitochondria. However, more studies are still necessary to provide the functional connections between mitochondria and the female reproductive system. Presentation: Saturday, June 17, 2023

Therapeutic Targeting of Mitochondrial Plasticity and Redox Control to Overcome Cancer Chemoresistance.

Mitochondria are subcellular organelles performing essential metabolic functions contributing to cellular bioenergetics and regulation of cell growth or death. The basic mitochondrial function in fulfilling the need for cell growth and vitality is evidenced by the conditional state whereby cancer cells with depleted mitochondrial DNA (rho zero cells) are no longer capable of forming tumors until newly recruited mitochondria are internalized into the rho zero cells. Herein lies the absolute dependency on mitochondria for tumor growth. In addition, mitochondria are key regulators of cell death (by apoptosis, necroptosis, or other forms of cell death) and are therefore important targets for anticancer therapy. Mitochondrial plasticity regulating their state of fusion or fission is also key to the chemoresistance properties of cancer cells by promoting pro-survival pathways enabling the mitochondria to mitigate against the cellular stresses and extreme conditions within the tumor microenvironment caused by chemotherapy, hypoxia, or oxidative stress. This review discusses many characteristics of mitochondria, the processes and pathways controlling the dynamic changes occurring in the morphology of mitochondria, the roles of reactive oxygen species, and their relationship with mitochondrial fission or fusion. It also examines the relationship of redox to mitophagy when mitochondria become compromised and its effect on cancer cell survival, stemness and the changes accompanying malignant progression from primary tumors to metastatic disease. A challenging question that arises is whether the changes in mitochondrial dynamics and their regulation can provide opportunities for improving drug targeting during cancer treatment and enhancing survival outcomes.

Abstract P1095: Studying Changes In Mitochondrial Dynamics And Energetics During Cardiac Reprogramming

In mammals, cardiac ischemic injury leads to loss of muscle filled in with less functional scar tissue. Direct reprogramming of the cardiac fibroblasts populating a scar to functional cardiomyocytes represents a promising potential treatment for these patients. This reprogramming involves a metabolic shift from the more glycolytic CF state to mitochondrial oxidative phosphorylation in the induced CMs, including increased mitochondrial biogenesis. Various reprogramming strategies make use of agents, which in addition to canonical roles, promote mitochondrial energetics and a dynamic shift towards mitochondrial fusion. We decided to investigate whether these mitochondrial structural and functional shifts might represent a mechanism of reprogramming. We characterized various structural and energetic properties of mitochondria in neonatal CFs, CMs, and at multiple time points during reprogramming. Using the baseline CF and CM mitochondrial data, we built a model to follow cells in pseudotime during reprogramming, and identified a time course for mitochondrial changes. We also investigated whether various mitochondrial perturbations designed to promote these changes might increase reprogramming efficiency. Promotion of mitochondrial fusion activity and biogenesis increased the proportion of reprogrammed cells. Conversely, promotion of fission and inhibitors for electron transport system enzymes inhibited reprogramming.

Manipulating mitochondrial dynamics in the NTS prevents diet-induced deficits in brown fat morphology and glucose uptake

AimsBrown adipose tissue (BAT) can produce heat by metabolizing glucose and fatty acids. Activation of BAT is controlled by the central nervous system (CNS) through sympathetic innervation. Dysregulation of signalling molecules in selective CNS areas such as the nucleus of tractus solitarius (NTS) are linked with altered BAT activity, obesity and diabetes. High-fat diet (HFD)-feeding increases mitochondrial fragmentation in the NTS, triggering insulin resistance, hyperphagia and weight gain. Here we sought to determine whether changes in mitochondrial dynamics in the NTS can affect BAT glucose uptake. Main methodsRats received DVC stereotactic surgery for local brain administration of viruses that express mutated Drp1 genes. BAT glucose uptake was measured with PET/CT scans. Biochemical assays and immunohistochemistry determined altered levels of key signalling molecules and neural innervation of BAT. Key findingsWe show that short-term HFD-feeding decreases BAT glucose uptake. However, inhibiting mitochondrial fragmentation in NTS-astrocytes of HFD-fed rats partially restores BAT glucose uptake accompanied by lower blood glucose and insulin levels. Tyrosine Hydroxylase (TH) revealed that rats with inhibited mitochondrial fragmentation in NTS astrocytes had higher levels of catecholaminergic innervation in BAT compared to HFD-fed rats, and did not exhibit HFD-dependent infiltration of enlarged white fat droplets in the BAT. In regular chow-fed rats, increasing mitochondrial fragmentation in the NTS-astrocytes reduced BAT glucose uptake, TH immune-positive boutons and β3-adrenergic receptor levels. SignificanceOur data suggest that targeting mitochondrial dynamics in the NTS-astrocytes could be a beneficial strategy to increase glucose utilization and protect from developing obesity and diabetes.

Novel insights into the role of mitochondria in diabetic cardiomyopathy: molecular mechanisms and potential treatments.

Diabetic cardiomyopathy describes decreased myocardial function in diabetic patients in the absence of other heart diseases such as myocardial ischemia and hypertension. Recent studies have defined numerous molecular interactions and signaling events that may account for deleterious changes in mitochondrial dynamics and functions influenced by hyperglycemic stress. A metabolic switch from glucose to fatty acid oxidation to fuel ATP synthesis, mitochondrial oxidative injury resulting from increased mitochondrial ROS production and decreased antioxidant capacity, enhanced mitochondrial fission and defective mitochondrial fusion, impaired mitophagy, and blunted mitochondrial biogenesis are major signatures of mitochondrial pathologies during diabetic cardiomyopathy. This review describes the molecular alterations underlying mitochondrial abnormalities associated with hyperglycemia and discusses their influence on cardiomyocyte viability and function. Based on basic research findings and clinical evidence, diabetic treatment standards and their impact on mitochondrial function, as well as mitochondria-targeted therapies of potential benefit for diabetic cardiomyopathy patients, are also summarized.

Effect of Exercise and Oral Niacinamide Mononucleotide on Improving Mitochondrial Autophagy in Alzheimer's Disease.

Oral niacinamide mononucleotide (NMN) and aerobic exercise have been shown to enhance niacinamide adenine dinucleotide (NAD+) in the body. NAD+ plays a critical role in the body and can directly and indirectly affect many key cellular functions, including metabolic pathways, DNA repair, chromatin remodeling, cell aging, and immune cell function. It is noteworthy that the level of NAD+ decreases gradually with increasing age. Decreased levels of NAD+ have been causally associated with a number of diseases associated with aging, including cognitive decline, cancer, metabolic diseases, sarcopenia, and frailty. Many diseases related to aging can be slowed down or even reversed by restoring NAD+ levels. For example, oral NMN or exercise to increase NAD+ levels in APP/PS1 mice have been proven to improve mitochondrial autophagy, but currently, there is no regimen combining oral NMN with exercise. This review summarizes recent studies on the effect of oral NMN on the enhancement of NAD+ in vivo and the improvements in mitochondrial autophagy abnormalities in AD through aerobic exercise, focusing on (1) how oral NMN improves the internal NAD+ level; (2) how exercise regulates the content of NAD+ in the body; (3) the relationship between exercise activation of NAD+ and AMPK; (4) how SIRT1 is regulated by NAD+ and AMPK and activates PGC-1α to mediate mitochondrial autophagy through changes in mitochondrial dynamics. By summarizing the results of the above four aspects, and combined with the synthesis of NAD+ in vivo, we can infer how exercise elevates the level of NAD+ in vivo to mediate mitochondrial autophagy, so as to propose a new hypothesis that exercise interferes with Alzheimer's disease (AD).