Soluble, Prefibrillar α-Synuclein Oligomers Promote Complex I-dependent, Ca2+-induced Mitochondrial Dysfunction

Luth, Eric S.; Stavrovskaya, Irina G.; Bartels, Tim; Kristal, Bruce S.; Selkoe, Dennis J.

doi:10.1074/jbc.m113.545749

Cited by 239 publications

(180 citation statements)

References 82 publications

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“…We next treated mitochondria with sequential additions of calcium (26). Each calcium addition could be observed as an increase in Calcium Green fluorescence in the buffer, whereas uptake into the organelles was reflected in a reduction in buffer calcium (Fig.…”

Section: Significancementioning

confidence: 99%

UCP1 deficiency causes brown fat respiratory chain depletion and sensitizes mitochondria to calcium overload-induced dysfunction

Kazak

Chouchani

Stavrovskaya

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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142

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Brown adipose tissue (BAT) mitochondria exhibit high oxidative capacity and abundant expression of both electron transport chain components and uncoupling protein 1 (UCP1). UCP1 dissipates the mitochondrial proton motive force (Δp) generated by the respiratory chain and increases thermogenesis. Here we find that in mice genetically lacking UCP1, cold-induced activation of metabolism triggers innate immune signaling and markers of cell death in BAT. Moreover, global proteomic analysis reveals that this cascade induced by UCP1 deletion is associated with a dramatic reduction in electron transport chain abundance. UCP1-deficient BAT mitochondria exhibit reduced mitochondrial calcium buffering capacity and are highly sensitive to mitochondrial permeability transition induced by reactive oxygen species (ROS) and calcium overload. This dysfunction depends on ROS production by reverse electron transport through mitochondrial complex I, and can be rescued by inhibition of electron transfer through complex I or pharmacologic depletion of ROS levels. Our findings indicate that the interscapular BAT of Ucp1 knockout mice exhibits mitochondrial disruptions that extend well beyond the deletion of UCP1 itself. This finding should be carefully considered when using this mouse model to examine the role of UCP1 in physiology.brown fat | mitochondria | ROS | UCP1 | electron transport chain U ncoupling protein 1 (UCP1) plays a role in acute adaptive thermogenesis in interscapular brown adipose tissue (BAT). UCP1 dissipates the mitochondrial protonmotive force (Δp) generated by the electron transport chain (ETC) and is important for thermal homeostasis in rodents and human infants (1, 2). Ucp1 orthologs are not limited to mammals, but are also expressed in ectothermic vertebrates (3) and protoendothermic mammals (4), suggesting that UCP1 may have an important role in biology beyond thermal control. For example, it is becoming increasingly evident that in specific respiratory states, UCP1 can reduce reactive oxygen species (ROS) levels in vitro (4-9). The mitochondrial ETC is a major source of ROS production in the cell, and ROS play important roles in physiology and pathophysiology (10-12). Reverse electron transport (RET) through mitochondrial complex I is a key mechanism by which ROS are generated in vivo (11, 13). Interestingly, RET relies critically on high Δp, whereas dissipation of Δp by UCP1 can lower ROS levels in isolated mitochondria (5-7).Thermogenic respiration in BAT is triggered by external stimuli that activate adrenergic signaling (14). Most notably, environmental cold induces the capacity for adrenergic-mediated BAT respiration in wild type (WT) animals, but only minimally in UCP1-KO animals (15, 16). It is understood that the respiratory response of BAT under these conditions is indicative of UCP1-mediated respiration; however, the rate of maximal chemically uncoupled oxygen consumption, an UCP1-independent parameter, is also lower in UCP1-KO adipocytes compared with WT (15, 16).Moreover, the basal respiratory rat...

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Section: Significancementioning

confidence: 99%

UCP1 deficiency causes brown fat respiratory chain depletion and sensitizes mitochondria to calcium overload-induced dysfunction

Kazak

Chouchani

Stavrovskaya

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

142

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“…Deeply, according to the information above, the mitochondrial dysfunction exists both in α-syn overexpression models and in CTIQs treated models [25,38,46,47,49,50,65,66,78,82,[137][138][139][140]. Therefore, the contribution of α-syn and CTIQs to the pathogenesis of PD could both ascribe to the damaged mitochondria, which further verified the interrelation between CTIQs and α-syn.…”

Section: Ctiqs and α-Syn Aggregationmentioning

confidence: 94%

“…Many mitochondria exist in the synapses of Dopaminergic neurons, the impairment of which is an initial step for cell apoptosis. In this mechanism, aggregated α-syn can interact with mitochondrial membranes and further induce the release of respiratory protein cytochrome c, an increase of mitochondrial calcium, complex I dysfunction, a decrease of membrane potential and mitochondrial swelling, finally leading to the mitochondrial dysfunction [137][138][139][140]. And mitochondrial dysfunction can generate the excessive ROS and eventually induce death of dopaminergic neuron [141].…”

Section: α-Synuclein Aggregation and Parkinson Diseasementioning

confidence: 99%

Catechol Tetrahydroisoquinolines Enhance a-Synuclein Aggregation and Specify the Neurotoxicity to Dopaminergic Neurons

Chen¹,

Lu²,

Duan³

et al. 2017

J Alzheimers Dis Parkinsonism

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“…α-Synuclein (α-syn) is a cellular acidic protein of 140 amino acid residues that release neurotransmitters in the presynaptic nerve terminals [1][2][3][4] and whose abnormal aggregation results at the onset of Parkinson's disease (PD) [5][6][7][8][9]. Accumulation of α-syn fibrils in neuronal inclusions is the major pathological process involved in PD.…”

Section: Introductionmentioning

confidence: 99%

Effect of C-Terminal Truncations on the Aggregation Propensity of Α- Synuclein - A Potential of Mean Force Study

Sanjeev¹,

Mattaparthi²

2017

J Mol Imaging Dynam

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Abstractα-Synuclein is an intrinsically disordered protein which has a prominent role in Parkinson's disease (PD). Several familial variants of α-synuclein have been reported to associate with inherited PD. Several studies have highlighted the presence and association of the C-terminus of truncated forms of α-synuclein with Wild type α-synuclein (WT α-syn) at much higher level in patients with Lewy body diseases and they are found to decrease the reductive capabilities and potentially results in permanent oxidation of α-synuclein. To understand the impact of C-terminal truncations on the aggregation propensity of WT α-syn, the inter-molecular interactions between them are critical. Here we demonstrate the interactions between the WT α-syn and its three C-terminal truncations 95 (α-syn 95), 120 (α-syn 120) and 123 (α-syn 123), using Molecular Dynamics Simulations and Potential of Mean Force study (PMF). From the PMF study, we observed C-terminal truncation 120 (α-syn 120) to bind strongly to WT α-syn than the other truncated forms of α-synuclein. We also noticed number of hydrogen bonds to be larger, high geometrical shape complementarity score, larger number of interface residues and interface area for the hetero-dimer (WT α-syn-α-syn 120) than other hetero-dimers (WT α-syn -α-syn 95/123). We therefore can infer that among α-syn 95, α-syn 120 and α-syn 123, α-syn 120 to show more association with WT α-syn. This is because in α-syn 120, more amino acids have been removed in comparison to α-syn 123. In contrast, α-Syn 95 shows less interaction with WT α-syn because of the absence of the entire C-terminal region. Our findings suggest that more the truncation on the Cterminal region of α-synuclein more will the effect on its aggregation.

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Soluble, Prefibrillar α-Synuclein Oligomers Promote Complex I-dependent, Ca2+-induced Mitochondrial Dysfunction

Cited by 239 publications

References 82 publications

UCP1 deficiency causes brown fat respiratory chain depletion and sensitizes mitochondria to calcium overload-induced dysfunction

UCP1 deficiency causes brown fat respiratory chain depletion and sensitizes mitochondria to calcium overload-induced dysfunction

Catechol Tetrahydroisoquinolines Enhance a-Synuclein Aggregation and Specify the Neurotoxicity to Dopaminergic Neurons

Effect of C-Terminal Truncations on the Aggregation Propensity of Α- Synuclein - A Potential of Mean Force Study

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