Browsing by Author "Chen, Hao"
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Item Amyloid Beta-Mediated KIF5A Deficiency Disrupts Anterograde Axonal Mitochondrial Movement(Academic Press Inc.) Wang, Qi; Tian, Jing; Chen, Hao; Du, Heng; Guo, Lan; Wang, Qi; Tian, Jing; Chen, Hao; Du, Heng; Guo, LanMitochondria are crucial organelles for neurophysiology and brain mitochondrial defects constitute a characteristic of Alzheimer's disease (AD). Impaired axonal mitochondrial traffic, especially the anterograde axonal mitochondrial transport is a pronouncing mitochondrial defect that underlies synaptic failure in AD-related conditions. However, the detailed molecular mechanisms of such axonal mitochondrial abnormality have not been fully understood. KIF5A is a key isoform of kinesin-1, which is a key molecular machinery in facilitating anterograde axonal mitochondrial transport. In this study, we have determined a downregulation of KIF5A in postmortem AD temporal lobes. Further experiments on amyloid beta (Aβ)-treated primary neuron culture and 5 × FAD mice suggest a close association of Aβ toxicity and KIF5A loss. Downregulation of KIF5A mimics Aβ-induced axonal mitochondrial transport deficits, indicating a potential role of KIF5A deficiency in AD-relevant axonal mitochondrial traffic abnormalities. Importantly, the restoration of KIF5A corrects Aβ-induced impairments in axonal mitochondrial transport, especially the anterograde traffic, with little or no impact on retrograde axonal mitochondrial motility. Our findings suggest a novel KIF5A-associated mechanism conferring Aβ toxicity to axonal mitochondrial deficits. Furthermore, the results implicate a potential therapeutic avenue by protecting KIF5A function for the treatment of AD. © 2019 Elsevier Inc.Item Cyclophilin D Deficiency Attenuates Mitochondrial F1Fo ATP Synthase Dysfunction Via OSCP In Alzheimer's Disease(Academic Press Inc Elsevier Science, 2018-09-26) Gauba, Esha; Chen, Hao; Guo, Lan; Du, Heng; Gauba, Esha; Chen, Hao; Guo, Lan; Du, HengMitochondrial dysfunction is pivotal in inducing synaptic injury and neuronal stress in Alzheimer's disease (AD). Mitochondrial F1Fo ATP synthase deregulation is a hallmark mitochondrial defect leading to oxidative phosphorylation (OXPHOS) failure in this neurological disorder. Oligomycin sensitivity conferring protein (OSCP) is a crucial F1Fo ATP synthase subunit. Decreased OSCP levels and OSCP interaction with amyloid beta (A beta) constitute key aspects of F1Fo ATP synthase pathology in AD-related conditions. However, the detailed mechanisms promoting such AD-related OSCP changes have not been fully resolved. Here, we have found increased physical interaction of OSCP with Cyclophilin D (CypD) in AD cases as well as in an AD animal model (5xFAD mice). Genetic depletion of CypD mitigates OSCP loss via ubiquitin-dependent OSCP degradation in 5xFAD mice. Moreover, the ablation of CypD also attenuates OSCP/A beta interaction in AD mice. The relieved OSCP changes by CypD depletion in 5xFAD mice are along with preserved F1Fo ATP synthase function, restored mitochondrial bioenergetics as well as improved mouse cognition. The simplest interpretation of our results is that CypD is a critical mediator that promotes OSCP deficits in AD-related conditions. Therefore, to block the deleterious impact of CypD on OSCP has the potential to be a promising therapeutic strategy to correct mitochondrial dysfunction for AD therapy.Item Mitochondria-Dependent Local Caspase Activation and Mitofusin 2-Mediated Mitophagy in Neurodegeneration(2020-12-03) Chen, Hao; Du, HengMitochondria are critical regulators of neuronal physiology. They play a pivotal role in energy supply and Ca2+ buffering. Thus, mitochondria can sustain the synapse and neuronal function. In this regard, the mitochondria with an impaired capacity of bioenergetics or Ca2+ buffering will lead to synapse failure and neurodegeneration. Moreover, emerging evidence has shown that damaged mitochondria are also involved in local caspase activation, which coincides with spine pruning and neurodegeneration. However, the impacts of local caspase signaling on spine dynamics and neurodegeneration are still not clarified. To clarify them is critical for neurological disorders, in which the mitochondrial deficits are prominent and hard to be fixed. Additionally, as a pivotal mitochondrial enzyme – the F1Fo ATP synthase, dysfunction of it will lead to diseases with spinopathy. To this end, we inhibited the F1Fo ATP synthase by applying the sublethal oligomycin A to primary cultured neurons. Then, it induced the mitochondrial dysfunction and local caspase signaling. Following this, we blocked the caspase signaling through its inhibitor to determine whether it can rescue the spine elimination. In this case, we can dissect the caspase signaling out of mitochondrial energy supply and examine how much the caspase signaling attributes to spine pruning. Furthermore, we will find new ways to prevent the senescence of neurons through caspase inhibition. Moreover, mitochondrial quality control is of paramount importance for neuronal survival. Notably, mitophagy is a vital mechanism for maintenance of mitochondrial quality control. A previous study has shown that Mitofusin2 (Mfn2) plays a key role in mediating mitophagy in cardiomyocytes, which was demonstrated by decreased mitophagy in Mfn2 knockdown cardiomyocytes. In addition, lowered expression levels of Mfn2 have been repeatedly found in many neurodegenerative diseases like Alzheimer’s disease, which is characterized by the accumulation of damaged mitochondrial and mitophagosomes in neurons. In this regard, reduced Mfn2 expression may lead to compromised mitophagy and mitochondrial quality control. However, whether Mfn2 is indispensable for facilitating mitophagy has not been fully investigated. To this end, we knocked down Mfn2 in primary cultured neurons. Then, we examined the state of mitophagy. Intriguingly, we observed more mitophagosomes formation in Mfn2 knock-down neurons. It indicates the Mfn2 is not necessary for mitophagy induction. Such discrepancy may arise from the heterogeneity of different cell types. Also, it may arise from some alternative adaptor proteins, which can activate mitophagy. From previous reports, people pulled down the conjugated proteins from the outer mitochondrial membrane (OMM) of senescent and healthy neurons. After screening them by mass spectrum, they found that several OMM proteins may be the potential receptors for mitophagosome formation. Among them, Voltage-Dependent Anion Channel (VDAC) is the one most reported for mitophagy induction. Accordingly, we will further knockdown VDAC in Mfn2 knock-down neurons and examine the mitophagy states. In this case, we can determine whether VDAC can work as an Mfn2-independent alternative trigger for mitophagy in neurons. In all, both local caspases signaling and mitophagy play essential roles in neurodegeneration. Regulation of them may provide us new avenues for treating neurodegenerative diseases.Item Oestrogen Receptors Interact with the α-Catalytic Subunit of AMP-Activated Protein Kinase(Portland Press on behalf of the Biochemical Society) Lipovka, Yulia; Chen, Hao; Vagner, Josef; Price, Theodore J. (UT Dallas); Tsao, Tsu-Shuen; Konhilas, John P.Normal and pathological stressors engage the AMP-activated protein kinase (AMPK) signaling axis to protect the cell from energetic pressures. Sex steroid hormones also play a critical role in energy metabolism and significantly modify pathological progression of cardiac disease, diabetes/obesity, and cancer. AMPK is targeted by17β-estradiol (E2), the main circulating estrogen, but the mechanism by which E2 activates AMPK is currently unknown. Using an estrogen receptor α/β (ERα/β) positive (T47D) breast cancer cell line, we validated E2-dependent activation of AMPK that was mediated through ERα (not ERβ) by using three experimental strategies. A series of co-immunoprecipitation experiments showed that both ERs associated with AMPK in cancer and striated (skeletal and cardiac) muscle cells. We further demonstrated direct binding of ERs to the α-catalytic subunit of AMPK within the βγ-subunit binding domain. Finally, both ERs interacted with the upstream LKB1 kinase complex, which is required for E2-dependent activation of AMPK. We conclude that estradiol activates AMPK through ERα by direct interaction with the βγ-binding domain of AMPKα.; Copyright 2015 The Author(s).