Genetic reduction of mitochondrial complex I function does not lead to loss of dopamine neurons in vivo

Abstract Background Mitochondrial electron transport chain abnormalities have been reported in postmortem pathological specimens of Alzheimer’s disease (AD). However, it remains unclear how amyloid and tau are associated with mitochondrial dysfunction in vivo. The purpose of this study is to assess the local relationships between mitochondrial dysfunction and AD pathophysiology in mild AD using the novel mitochondrial complex I PET imaging agent [18F]BCPP-EF. Methods Thirty-two amyloid and tau positive mild stage AD dementia patients (mean age ± SD: 71.1 ± 8.3 years) underwent a series of PET measurements with [18F]BCPP-EF mitochondrial function, [11C]PBB3 for tau deposition, and [11C] PiB for amyloid deposition. Age-matched normal control subjects were also recruited. Inter and intrasubject comparisons of levels of mitochondrial complex I activity, amyloid and tau deposition were performed. Results The [18F]BCPP-EF uptake was significantly lower in the medial temporal area, highlighting the importance of the mitochondrial involvement in AD pathology. [11C]PBB3 uptake was greater in the temporo-parietal regions in AD. Region of interest analysis in the Braak stage I-II region showed significant negative correlation between [18F]BCPP-EF SUVR and [11C]PBB3 BPND (R = 0.2679, p = 0.04), but not [11C] PiB SUVR. Conclusions Our results indicated that mitochondrial complex I is closely associated with tau load evaluated by [11C]PBB3, which might suffer in the presence of its off-target binding. The absence of association between mitochondrial complex I dysfunction with amyloid load suggests that mitochondrial dysfunction in the trans-entorhinal and entorhinal region is a reflection of neuronal injury occurring in the brain of mild AD.

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Unique responses to mitochondrial complex I inhibition in tuberoinfundibular dopamine neurons may impart resistance to toxic insult

Neuroscience ◽

10.1016/j.neuroscience.2007.05.007 ◽

2007 ◽

Vol 147 (3) ◽

pp. 592-598 ◽

Cited By ~ 18

Author(s):

B. Behrouz ◽

R.E. Drolet ◽

Z.A. Sayed ◽

K.J. Lookingland ◽

J.L. Goudreau

Keyword(s):

Complex I ◽

Dopamine Neurons ◽

Mitochondrial Complex I ◽

Mitochondrial Complex

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In vivo induction of heat shock proteins in the substantia nigra following L-DOPA administration is associated with increased activity of mitochondrial complex I and nitrosative stress in rats: regulation by glutathione redox state

Journal of Neurochemistry ◽

10.1111/j.1471-4159.2006.04367.x ◽

2007 ◽

Vol 101 (3) ◽

pp. 709-717 ◽

Cited By ~ 43

Author(s):

Vittorio Calabrese ◽

Cesare Mancuso ◽

Agrippino Ravagna ◽

Marzia Perluigi ◽

Chiara Cini ◽

...

Keyword(s):

Complex I ◽

Redox State ◽

Nitrosative Stress ◽

Mitochondrial Complex I ◽

Mitochondrial Complex ◽

Shock Proteins ◽

Increased Activity ◽

Glutathione Redox ◽

In Vivo Induction

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Molecular mechanism and physiological role of active–deactive transition of mitochondrial complex I

Biochemical Society Transactions ◽

10.1042/bst20130088 ◽

2013 ◽

Vol 41 (5) ◽

pp. 1325-1330 ◽

Cited By ~ 21

Author(s):

Marion Babot ◽

Alexander Galkin

Keyword(s):

Complex I ◽

Physiological Role ◽

Protective Mechanism ◽

Mitochondrial Complex I ◽

Mitochondrial Complex ◽

The Status ◽

Nitric Oxide Metabolites

The unique feature of mitochondrial complex I is the so-called A/D transition (active–deactive transition). The A-form catalyses rapid oxidation of NADH by ubiquinone (k ~104 min−1) and spontaneously converts into the D-form if the enzyme is idle at physiological temperatures. Such deactivation occurs in vitro in the absence of substrates or in vivo during ischaemia, when the ubiquinone pool is reduced. The D-form can undergo reactivation given both NADH and ubiquinone availability during slow (k ~1–10 min−1) catalytic turnover(s). We examined known conformational differences between the two forms and suggested a mechanism exerting A/D transition of the enzyme. In addition, we discuss the physiological role of maintaining the enzyme in the D-form during the ischaemic period. Accumulation of the D-form of the enzyme would prevent reverse electron transfer from ubiquinol to FMN which could lead to superoxide anion generation. Deactivation would also decrease the initial burst of respiration after oxygen reintroduction. Therefore the A/D transition could be an intrinsic protective mechanism for lessening oxidative damage during the early phase of reoxygenation. Exposure of Cys39 of mitochondrially encoded subunit ND3 makes the D-form susceptible for modification by reactive oxygen species and nitric oxide metabolites which arrests the reactivation of the D-form and inhibits the enzyme. The nature of thiol modification defines deactivation reversibility, the reactivation timescale, the status of mitochondrial bioenergetics and therefore the degree of recovery of the ischaemic tissues after reoxygenation.

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In vivo chlorophyll fluorescence screening allows the isolation of a Chlamydomonas mutant defective for NDUFAF3, an assembly factor involved in mitochondrial complex I assembly

The Plant Journal ◽

10.1111/tpj.13677 ◽

2017 ◽

Vol 92 (4) ◽

pp. 584-595 ◽

Cited By ~ 5

Author(s):

Simon Massoz ◽

Marc Hanikenne ◽

Benjamin Bailleul ◽

Nadine Coosemans ◽

Michèle Radoux ◽

...

Keyword(s):

Chlorophyll Fluorescence ◽

Complex I ◽

Mitochondrial Complex I ◽

Mitochondrial Complex ◽

Assembly Factor ◽

Complex I Assembly ◽

In Vivo Chlorophyll Fluorescence

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Intrastriatal Neurotoxin Injections Reduce in Vitro and in Vivo Binding of Radiolabeled Rotenoids to Mitochondrial Complex I

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-199703000-00003 ◽

1997 ◽

Vol 17 (3) ◽

pp. 265-272 ◽

Cited By ~ 10

Author(s):

Michael R. Kilbourn ◽

Avgui Charalambous ◽

Kirk A. Frey ◽

Phillip Sherman ◽

Donald S. Higgins ◽

...

Keyword(s):

Quinolinic Acid ◽

Complex I ◽

Rat Striatum ◽

Mitochondrial Complex I ◽

Mitochondrial Complex ◽

In Vivo Binding ◽

Vitro Binding ◽

Direct Competition

The in vivo and in vitro bindings of radiolabeled rotenoids to mitochondrial complex I of rat striatum were examined after unilateral intrastriatal injections of quinolinic acid or 1-methyl-4-phenylpyridinium salt (MPP+). Quinolinic acid produced significant, similar losses of in vivo binding of [11C]dihydrorotenol ([11C]DHROL: 40%) and in vitro binding of [3H]dihydrorotenone ([3H]DHR: 53%) in the injected striata at 13 days after the injection of neurotoxin. MPP+ reduced in vivo binding of [11C]DHROL (up to −55%) as measured 1.5 to 6 h after its administration. Reductions of in vivo [11C]DHROL binding after either quinolinic acid or MPP+ injections did not correlate with changes in striatal blood flow as measured with [14C]iodoantipyrine. These results are consistent with losses of complex I binding sites for radiolabeled rotenoids, produced using cell death (quinolinic acid) or direct competition for the binding site (MPP+). Appropriately radiolabeled rotenoids may be useful for in vivo imaging studies of changes of complex I in neurodegenerative diseases.

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In Vivo Labeling of Mitochondrial Complex I (NADH:UbiquinoneOxidoreductase) in Rat Brain Using [3H]Dihydrorotenone

Journal of Neurochemistry ◽

10.1046/j.1471-4159.2000.0752611.x ◽

2008 ◽

Vol 75 (6) ◽

pp. 2611-2621 ◽

Cited By ~ 80

Author(s):

Deepa J. Talpade ◽

James G. Greene ◽

Donald S. Higgins ◽

J. Timothy Greenamyre

Keyword(s):

Rat Brain ◽

Complex I ◽

Mitochondrial Complex I ◽

Mitochondrial Complex ◽

In Vivo Labeling

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Cyclosporine augments renal mitochondrial function in vivo and reduces renal blood flow

AJP Renal Physiology ◽

10.1152/ajprenal.1989.257.5.f837 ◽

1989 ◽

Vol 257 (5) ◽

pp. F837-F841 ◽

Cited By ~ 2

Author(s):

C. A. Lemmi ◽

P. C. Pelikan ◽

S. C. Sikka ◽

R. Hirschberg ◽

B. Geesaman ◽

...

Keyword(s):

Blood Flow ◽

Renal Blood Flow ◽

Complex I ◽

Atp Synthesis ◽

Treated Group ◽

Mitochondrial Complex I ◽

Mitochondrial Oxidative Phosphorylation ◽

Mitochondrial Complex ◽

Complex I Activity

The in vivo action of cyclosporine A (CS) on rat renal cortical mitochondria was investigated. CS (30 mg.kg-1.day-1) given orally to rats for 30 days caused an augmentation of renal mitochondrial oxidative phosphorylation. The ADP-stimulated respiratory rate was increased by 37.0% with glutamate plus malate as respiratory substrates (P less than 0.025) but not with succinate-supported respiration, indicating enhancement of mitochondrial complex I activity. This reaction may be a response to the 32.5% reduction of renal blood (P less than 0.005) in the CS-treated group, possibly serving to maximize ATP synthesis during ischemia. Ligation-induced decreases in renal blood flow also resulted in enhancement of mitochondrial complex I activity.

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Taxifolin Alleviates Metabolic and Neurochemical Alterations in Hippocampus and Cortex of Brain of Rotenone-Toxified Rats in Vivo and Effectively Interacts with Enzymes Involve in Neurotransmission in Silico

10.21203/rs.3.rs-514482/v1 ◽

2021 ◽

Author(s):

Sunday Solomon JOSIAH ◽

Ibrahim Olabayode Saliu ◽

Haruna Isiyaku Umar ◽

Courage Dele Famusiwa ◽

Afolabi Clement Akinmoladun

Keyword(s):

Oxidative Stress ◽

Tyrosine Hydroxylase ◽

Molecular Interaction ◽

In Silico ◽

Complex I ◽

Mitochondrial Complex I ◽

Mitochondrial Complex ◽

The Brain ◽

Neurotransmitter Metabolism

Abstract Rotenone is a naturally occurring compound and inhibitor of mitochondrial complex I. Its exposure is toxic and directly affects the function of mitochondrial which leads to neurodegeneration. Taxifolin is a flavonoid that exhibits therapeutic potentials in various neurodegenerative diseases via its anti-oxidative, anti-inflammatory and neuromodulatory properties. In this study, we evaluated the therapeutic potential of taxifolin to alleviate metabolic and neurochemical alterations in the hippocampal and cortical region of brain of rotenone-toxified rats in vivo and to assess its influence on some enzymes involve in neurotransmission in silico. Taxifolin (0.25, 0.5 and 1.0 mg/kg) was orally post-administered to male Wistar rats for 3 days after 10 days subcutaneous administration of rotenone. Activities of mitochondrial complex I, membrane ion pump and lactate dehydrogenase (LDH) were evaluated in the hippocampus and cortex of the brain of rotenone-toxified rats. Markers of neurotransmitter metabolism and oxidative stress were also biochemically estimated and molecular interaction between taxifolin and tyrosine hydroxylase, monoamine oxidase, glutamine synthetase and Na+K+ ATPase was determined by in silico simulation. Taxifolin attenuated dysfunction of mitochondrial, Na+K+ ATPase, LDH and modulate neurotransmitter metabolism. Also, the elicited oxidative stress was mitigated by taxifolin in the hippocampus and cortex of the brain of rotenone-toxified rats. The highest binding affinity was recorded in taxifolin and tyrosine hydroxylase complex. Hydrogen bond and hydrophobic interactions were the two key molecular interaction between the taxifolin and targeted enzymes. Thus, taxifolin significantly exert therapeutic effect against rotenone-induced neurotoxicity in rats via anti-oxidative, as well as mitochondrial and neurotransmitter modulatory activity.

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Loss of mitochondrial complex I activity potentiates dopamine neuron death induced by microtubule dysfunction in a Parkinson’s disease model

The Journal of Cell Biology ◽

10.1083/jcb.201009132 ◽

2011 ◽

Vol 192 (5) ◽

pp. 873-882 ◽

Cited By ~ 116

Author(s):

Won-Seok Choi ◽

Richard D. Palmiter ◽

Zhengui Xia

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Complex I ◽

Dopamine Neuron ◽

Dopamine Neurons ◽

Substantia Nigra Pars Compacta ◽

Mitochondrial Complex I ◽

Mitochondrial Complex ◽

Neuron Death ◽

Complex I Activity

Mitochondrial complex I dysfunction is regarded as underlying dopamine neuron death in Parkinson’s disease models. However, inactivation of the Ndufs4 gene, which compromises complex I activity, does not affect the survival of dopamine neurons in culture or in the substantia nigra pars compacta of 5-wk-old mice. Treatment with piericidin A, a complex I inhibitor, does not induce selective dopamine neuron death in either Ndufs4+/+ or Ndufs4−/− mesencephalic cultures. In contrast, rotenone, another complex I inhibitor, causes selective toxicity to dopamine neurons, and Ndufs4 inactivation potentiates this toxicity. We identify microtubule depolymerization and the accumulation of cytosolic dopamine and reactive oxygen species as alternative mechanisms underlying rotenone-induced dopamine neuron death. Enhanced rotenone toxicity to dopamine neurons from Ndufs4 knockout mice may involve enhanced dopamine synthesis caused by the accumulation of nicotinamide adenine dinucleotide reduced. Our results suggest that the combination of disrupting microtubule dynamics and inhibiting complex I, either by mutations or exposure to toxicants, may be a risk factor for Parkinson’s disease.

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