Mitochondrial ATP Synthase is a Target of Oxidative Stress in Neurodegenerative Diseases

Ebanks, Brad; Chakrabarti, Lisa

doi:10.3389/fmolb.2022.854321

Cited by 15 publications

(8 citation statements)

References 87 publications

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“…The latter was also provided by SPN ( Figure 4 ) as directly linked with the mitochondrial ATP synthase subunit beta (ATPB), a protein that we detected to be down-regulated in Het mice when compared to both Twi and WT animals ( Table 1 , Figure 2 , spot 14). Interestingly, ATPB is involved in lipoprotein uptake [ 108 ] and its expression was observed as increasing in Alzheimer’s and Huntington’s diseases [ 109 ].…”

Section: Resultsmentioning

confidence: 99%

Neurodegenerative Disorder Risk in Krabbe Disease Carriers

Vantaggiato

Shaba

Carleo

et al. 2022

IJMS

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Krabbe disease (KD) is a rare autosomal recessive disorder caused by mutations in the galactocerebrosidase gene (GALC). Defective GALC causes aberrant metabolism of galactolipids present almost exclusively in myelin, with consequent demyelinization and neurodegeneration of the central and peripheral nervous system (NS). KD shares some similar features with other neuropathies and heterozygous carriers of GALC mutations are emerging with an increased risk in developing NS disorders. In this work, we set out to identify possible variations in the proteomic profile of KD-carrier brain to identify altered pathways that may imbalance its homeostasis and that may be associated with neurological disorders. The differential analysis performed on whole brains from 33-day-old twitcher (galc −/−), heterozygous (galc +/−), and wild-type mice highlighted the dysregulation of several multifunctional factors in both heterozygous and twitcher mice. Notably, the KD-carrier mouse, despite its normal phenotype, presents the deregulation of vimentin, receptor of activated protein C kinase 1 (RACK1), myelin basic protein (MBP), 2′,3′-cyclic-nucleotide 3′-phosphodiesterase (CNP), transitional endoplasmic reticulum ATPase (VCP), and N-myc downstream regulated gene 1 protein (NDRG1) as well as changes in the ubiquitinated-protein pattern. Our findings suggest the carrier may be affected by dysfunctions classically associated with neurodegeneration: (i) alteration of (mechano) signaling and intracellular trafficking, (ii) a generalized affection of proteostasis and lipid metabolism, with possible defects in myelin composition and turnover, and (iii) mitochondrion and energy supply dysfunctions.

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Section: Resultsmentioning

confidence: 99%

Neurodegenerative Disorder Risk in Krabbe Disease Carriers

Vantaggiato

Shaba

Carleo

et al. 2022

IJMS

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“…Although Mitotracker and CellLight constructs are useful for examining the integrity and dynamics of the mitochondrial network, analysis of specific mitochondrial functions requires specialized tools to quantify ATP release, mitochondrial membrane potential, and calcium flux ( Iannetti et al, 2019 ). Altered expression of the mitochondrial ATP synthase has been reported in neurodegenerative diseases including AMD ( Nordgaard et al, 2008 ; Ebanks and Chakrabarti, 2022 ) but whether and to what extent these changes translate to impaired mitochondrial ATP production has yet to be established. To evaluate ATP generation in the RPE in realtime, we used BioTracker ATP-Red (Millipore).…”

Section: Resultsmentioning

confidence: 99%

Analysis of mitochondrial dynamics and function in the retinal pigment epithelium by high-speed high-resolution live imaging

Tan

Li²,

Germer³

et al. 2022

Front. Cell Dev. Biol.

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Mitochondrial dysfunction is strongly implicated in neurodegenerative diseases including age-related macular degeneration (AMD), which causes irreversible blindness in over 50 million older adults worldwide. A key site of insult in AMD is the retinal pigment epithelium (RPE), a monolayer of postmitotic polarized cells that performs essential functions for photoreceptor health and vision. Recent studies from our group and others have identified several features of mitochondrial dysfunction in AMD including mitochondrial fragmentation and bioenergetic defects. While these studies provide valuable insight at fixed points in time, high-resolution, high-speed live imaging is essential for following mitochondrial injury in real time and identifying disease mechanisms. Here, we demonstrate the advantages of live imaging to investigate RPE mitochondrial dynamics in cell-based and mouse models. We show that mitochondria in the RPE form extensive networks that are destroyed by fixation and discuss important live imaging considerations that can interfere with accurate evaluation of mitochondrial integrity such as RPE differentiation status and acquisition parameters. Our data demonstrate that RPE mitochondria show localized heterogeneities in membrane potential and ATP production that could reflect focal changes in metabolism and oxidative stress. Contacts between the mitochondria and organelles such as the ER and lysosomes mediate calcium flux and mitochondrial fission. Live imaging of mouse RPE flatmounts revealed a striking loss of mitochondrial integrity in albino mouse RPE compared to pigmented mice that could have significant functional consequences for cellular metabolism. Our studies lay a framework to guide experimental design and selection of model systems for evaluating mitochondrial health and function in the RPE.

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“…The ATP synthase is essential for ATP production and cellular energy metabolism. Defects of the ATP synthase and its assembly have been linked to various diseases [69][70][71] . Nevertheless, the assembly of the F 1 domain and the peripheral stalk of the mitochondrial ATP synthase is poorly understood.…”

Section: Discussionmentioning

confidence: 99%

The mitochondrial Hsp70 controls the assembly of the F1FO-ATP synthase

et al. 2023

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The mitochondrial F1FO-ATP synthase produces the bulk of cellular ATP. The soluble F1 domain contains the catalytic head that is linked via the central stalk and the peripheral stalk to the membrane embedded rotor of the FO domain. The assembly of the F1 domain and its linkage to the peripheral stalk is poorly understood. Here we show a dual function of the mitochondrial Hsp70 (mtHsp70) in the formation of the ATP synthase. First, it cooperates with the assembly factors Atp11 and Atp12 to form the F1 domain of the ATP synthase. Second, the chaperone transfers Atp5 into the assembly line to link the catalytic head with the peripheral stalk. Inactivation of mtHsp70 leads to integration of assembly-defective Atp5 variants into the mature complex, reflecting a quality control function of the chaperone. Thus, mtHsp70 acts as an assembly and quality control factor in the biogenesis of the F1FO-ATP synthase.

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Mitochondrial ATP Synthase is a Target of Oxidative Stress in Neurodegenerative Diseases

Cited by 15 publications

References 87 publications

Neurodegenerative Disorder Risk in Krabbe Disease Carriers

Neurodegenerative Disorder Risk in Krabbe Disease Carriers

Analysis of mitochondrial dynamics and function in the retinal pigment epithelium by high-speed high-resolution live imaging

The mitochondrial Hsp70 controls the assembly of the F1FO-ATP synthase

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