Browsing by Author "Gauba, Esha"
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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 Deregulation of Mitochondrial F1FO-ATP Synthase via OSCP in Alzheimer's Disease(Nature Publishing Group) Beck, Simon J.; Guo, Lan; Phensy, Aarron; Tian, Jing; Wang, Lu; Tandon, Neha; Gauba, Esha; Lu, Lin; Pascual, J. M.; Kroener, Sven; Du, Heng; 0000-0003-1728-8111 (Kroener, S); Beck, Simon J.; Guo, Lan; Phensy, Aarron; Tian, Jing; Wang, Lu; Tandon, Neha; Gauba, Esha; Lu, Lin; Kroener, Sven; Du, HengF1FO-ATP synthase is critical for mitochondrial functions. The deregulation of this enzyme results in dampened mitochondrial oxidative phosphorylation (OXPHOS) and activated mitochondrial permeability transition (mPT), defects which accompany Alzheimerâ (tm) s disease (AD). However, the molecular mechanisms that connect F1FO-ATP synthase dysfunction and AD remain unclear. Here, we observe selective loss of the oligomycin sensitivity conferring protein (OSCP) subunit of the F1FO-ATP synthase and the physical interaction of OSCP with amyloid beta (Aβ) in the brains of AD individuals and in an AD mouse model. Changes in OSCP levels are more pronounced in neuronal mitochondria. OSCP loss and its interplay with Aβ disrupt F1FO-ATP synthase, leading to reduced ATP production, elevated oxidative stress and activated mPT. The restoration of OSCP ameliorates Aβ-mediated mouse and human neuronal mitochondrial impairments and the resultant synaptic injury. Therefore, mitochondrial F1FO-ATP synthase dysfunction associated with AD progression could potentially be prevented by OSCP stabilization.Item Oligomycin Sensitivity Conferring Protein and Mitochondrial Deficits in the Aging Brain and Alzheimer's Disease(2019-01-10) Gauba, Esha; Du, HengBrain aging is the strongest risk factor for Alzheimer’s Disease (AD), in particular its sporadic form. However, the mechanism underlying the development of AD as a result of aging remains elusive. In recent years, mitochondrial deficits have been proposed to be a common mechanism linking brain aging to AD, and are considered pivotal in inducing synaptic injury and neuronal stress. Therefore, to elucidate the causative mechanisms of mitochondrial dysfunction in aging brains is of paramount importance for our understanding of the pathogenesis of AD. Cyclophilin D (CypD) is a specific mitochondrial protein. Recent studies have shown that F1FO ATP synthase oligomycin sensitivity conferring protein (OSCP) is a binding partner of CypD. The interaction of CypD with OSCP modulates F1FO ATP synthase function and mediates mitochondrial permeability transition pore (mPTP) opening. Here, we have found that increase in CypD expression, enhanced CypD/OSCP interaction and selective loss of OSCP are prominent brain mitochondrial changes in aging and AD mice. Furthermore, Aβ toxicity in AD-related pathophysiology augments CypD/OSCP interaction and exacerbates mitochondrial dysfunction. Moreover, the ablation of CypD relieves OSCP changes in the aging brain and 5xFAD mice along with preserved F1FO ATP synthase function, restored mitochondrial bioenergetics as well as improved mouse cognition (in AD mice). This suggests that CypD is a regulator of OSCP expression and promotes OSCP deficits, which causes mitochondrial dysfunction in brain aging and AD-related conditions. To further support our findings of CypD-mediated OSCP changes in the development of mitochondrial deficits in AD, we restored OSCP expression in AD mice by utilizing an original neuron-specific OSCP overexpressing mice. OSCP overexpressing AD mice exhibited significant protection from F1FO ATP synthase deregulation. Importantly, such protection accompanies preserved mitochondrial bioenergetics and blunted mitochondrial permeability transition pore (mPTP) formation as well as restored synaptic plasticity and transmission & improved cognition in AD mice. Thus, our findings collectively suggest that OSCP-associated mitochondrial deficits are common mechanisms in brain aging and AD and preserving OSCP expression has the potential to be a promising therapeutic strategy to correct mitochondrial dysfunction in brain aging and AD.Item Transient Cerebral Ischemia Promotes Brain Mitochondrial Dysfunction and Exacerbates Cognitive Impairments in Young 5xFAD Mice(Public Library of Science, 2015-12-03) Lu, Lin; Guo, Lan; Gauba, Esha; Tian, Jing; Wang, Lu; Tandon, Neha; Shankar, Malini; Beck, Simon J.; Du, Yifeng; Du, Heng; Lu, Lin; Guo, Lan; Gauba, Esha; Tian, Jing; Wang, Lu; Tandon, Neha; Shankar, Malini; Beck, Simon J.; Du, HengAlzheimer's disease (AD) is heterogeneous and multifactorial neurological disorder; and the risk factors of AD still remain elusive. Recent studies have highlighted the role of vascular factors in promoting the progression of AD and have suggested that ischemic events increase the incidence of AD. However, the detailed mechanisms linking ischemic insult to the progression of AD is still largely undetermined. In this study, we have established a transient cerebral ischemia model on young 5xFAD mice and their non-transgenic (nonTg) littermates by the transient occlusion of bilateral common carotid arteries. We have found that transient cerebral ischemia significantly exacerbates brain mitochondrial dysfunction including mitochondrial respiration deficits, oxidative stress as well as suppressed levels of mitochondrial fusion proteins including optic atrophy 1 (OPA1) and mitofusin 2 (MFN2) in young 5xFAD mice resulting in aggravated spatial learning and memory. Intriguingly, transient cerebral ischemia did not induce elevation in the levels of cortical or mitochondrial Amyloid beta (Aß)1-40 or 1-42 levels in 5xFAD mice. In addition, the glucose- and oxygen-deprivation-induced apoptotic neuronal death in Aß-treated neurons was significantly mitigated by mitochondria-targeted antioxidant mitotempo which suppresses mitochondrial superoxide levels. Therefore, the simplest interpretation of our results is that young 5xFAD mice with pre-existing AD-like mitochondrial dysfunction are more susceptible to the effects of transient cerebral ischemia; and ischemic events may exacerbate dementia and worsen the outcome of AD patients by exacerbating mitochondrial dysfunction.;