Dysregulation of subunits of mitochondrial complex 1 plays a key role in MC1 dysfunction.

1. INVOLVEMENT OF
MITOCHONDRIAL COMPLEX-1 IN
PARKINSONS DISEASE
PRESENTED BY
Uppala sai Nikhil
RT/2021/614
MS(Pharm)1st yr
Regulatory toxicology
1 1

2. Parkinson’s disease
• Neuro degenerative disease.
• It predominantly affects the dopamine
secreting neurons in particular the substantia
nigra.
• mitochondrial complex 1 dysfunction is said to
contributing to parkinsonism.
PATHWAY AFFECTED
Nigrostriatal tract
INTRODUCTION
2
https://doi.org/10.3389/fnbeh.2016.00121
blueringmedia

3. MITOCHONDRIA and its structure
IN MITOCHONDRIAL MATRIX
NADH passes through complex 1,electrons thus produced
creates a protein gradient and thereby, ATP by oxidative
phosphorylation
TCA CYCLE
Pyruvate converted to acetyl coA which are then converted to
NADH and FAD
GLYCOLYSIS
Releases 2 pyruvate
3
Mohamed Yusoff, Abdul Aziz. (2015). Understanding Mitochondrial DNA in Brain Tumorigenesis.

4. ELECTRON TRANSPORT CHAIN
MECHANISM
Bailey, Regina. "Electron Transport Chain and Energy Production Explained." ThoughtCo, Feb. 7, 2021, thoughtco.com/electron-transport-chain-and-energy-production-4136143. 4
Hovde, Blake & Deodato, Chloe & Andersen, Robert & Starkenburg, Shawn & Barlow, Steven & Cattolico, Rose Ann. (2019). Chrysochromulina: Genomic assessment and taxonomic diagnosis of the type species for an oleaginous algal
clade. Algal Research. 37. 307-319. 10.1016/j.algal.2018.11.023.

5. COMPLEX-1
Metabolic role of complex 1 is to oxidize NADH to NAD+ where 2 electrons are released 4 protons are released into
inter membrane space
STRUCTURE AND ARCHITECHTURE
▪ L-shaped structure and has 45 subunits
SUPER NUMERARY SUBUNITS—protectIon from ROS
NADH UBIQUINONE OXIDOREDUCTASE
SUB UNITS
N-module P-module Q-module
31 –super
numerary
14 core
-----
-----
HYDROPHILIC
HYDROPHOBIC
Rutger O. Vogel, Jan A.M. Smeitink, Leo G.J. Nijtmans,Human mitochondrial complex I assembly: A dynamic and versatile process,Biochimica et Biophysica Acta (BBA) - Bioenergetics
5

6. 854M. Mimaki et al. / Biochimica et Biophysica Acta 1817 (2012) 851–862
FORMATION OF MITOCHONDRIAL COMPLEX-1
6
https://doi.org/10.1016/j.bbabio.2007.07.008

7. N-module
Q-module
P-module
• Dehydrogenase module
• Binds to NADH,captures electrons from oxidation
of NADH
• Hydrogenase module
• Electron transfer to ubiquinone
• Proton translocation module
• Binding of ubiquinone and proton pumping
FUNCTIONS OF SUBUNITS IN COMPLEX 1
• NDUFA9—Harbours NADH binding site
• ND1-provides protection from oxidative stress
7

8. Mt DNA
encoded sub
units
NUCLEAR DNA
Encoded sub
units
ND1
ND2
ND3
ND4
ND4L
ND5
ND6
NDUFV1
NDUFV2
NDUFS1
NDUFS2
NDUFS3
NDUFS7
NDUFS8
MITOCHONDRIAL c1 SUBUNIT DEFECTS THAT LEAD
TO DYSFUNCTION
NDUFV1 defect- causes hypersensitivity to oxidative stress
ND1 &ND5 deficiency-causes idiopathic parkinsonism
Hovde, Blake & Deodato, Chloe & Andersen, Robert & Starkenburg, Shawn & Barlow, Steven & Cattolico, Rose Ann. (2019). Chrysochromulina: Genomic assessment and taxonomic diagnosis of the type species
for an oleaginous algal clade. Algal Research. 37. 307-319. 10.1016/j.algal.2018.11.023.
8

9. COMPLEX 1 INVOLVEMENT IN PD
• In parkinsons disease nearly 42% of complex 1 dysregulation
occurs in mitochondria of substantia nigra
Majority of complex1 deficiency
occurs due to mutations in
genes such as
•
•
•
•
•
•
•
•
•
Compagnoni, Giacomo & Di Fonzo, Alessio & Corti, Stefania & Comi, Giacomo & Bresolin, Nereo & Masliah, Eliezer. (2020). The Role of Mitochondria in Neurodegenerative Diseases: the Lesson from Alzheimer’s Disease and Parkinson’s Disease. Molecular
Neurobiology. 57. 10.1007/s12035-020-01926-1.
9

10. EVIDENCES OF OXIDATIVE DAMAGE AT COMPLEX1
• In a research study brains are isolated from dead bodies of individuals where one of them suffers with
parkinsons disease
PATHOLOGICALLY
CONFIRMEDCONTROL
BRAIN
PARKINSONS BRAIN
Normal catalysis of NADH
at complex1
Decreased catalytic activity of
complex1
No change in level No change in levels
No significant change showed 11% increase in 20kda
protein and 33% reduction in 8kda
proteins compared to normal brain
LESS or No significant
amount
47% more when compared to normal
individuals
Proteins of
complexes 2-4
ND6 protein
Protein carbonyls
Paula M. Keeney, Jing Xie, Roderick A. Capaldi and James P. Bennett Jr Journal of Neuroscience 10 May 2006, 26 (19) 5256-5264; DOI: https://doi.org/10.1523/JNEUROSCI.0984-06.2006
10

11. • SO from the study it was found that there is a negative correlation between oxidative damage and
8Kda subunits of complex1
• Subunits that mainly suffer oxidative damage in complex1 are
Mt-DNA encoded subunits NuclearDNA encoded subunits
ND4
ND5
NDUFS1
NDUFS2
NDUFV1
NDUFB2
NDUFB6
NDUFB7
11

12. FUNCTIONS IMPAIRED
MITOCHONDRIAL C1
DYSFUNCTION
Increased oxidative stress
Reduced oxidative stress
response
Reduced ATP
production
Decreased UPS
function
Weak excitotoxicity
and increased free
radicles
APOPTOSIS
Grünewald, Anne & Kumar, Kishore & Sue, Carolyn. (2018). New insights into the complex role of mitochondria in Parkinson’s disease. Progress in Neurobiology. 177. 10.1016/j.pneurobio.2018.09.003.
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13. 13

14. MITO PARK MODEL:
Based on inactivation of MT transcription factor Tfam.
NUCLEAR GENOME Tfam gene Disruption
corresponding protein is imported to
mitochondria
DNA binding protein and aslo essential for
transcriptiom and maintainance of MT DNA
Decreased mt respiration
and respiratory chain
failure
1
Ekstrand, M. I., & Galter, D. (2009). The MitoPark Mouse - an animal model of Parkinson's disease with impaired respiratory chain function in dopamine neurons. Parkinsonism & related disorders, 15 Suppl 3, S185–S188.
https://doi.org/10.1016/S1353-8020(09)70811-9 14

15. CHEMICALLY INDUCED MODEL
MPTP treated mice model -
Heikkila et al., 1984, 1985; Markey et al., 1984; Javitch et al., 1985; Ramsey et al., 1986; Vays et al... 1986, Di Monte et al., 1986, Mizuno et al., 1987: Chiba et al 1988, Hasegawa, 1990, Cui et al., 2009..
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16. MPP at complex 1
prevents electron
flow to further
complexes
Electron
accumulation and
tranfered to mol
oxygen
ROS production
and oxidative
stress
Protein gradient
disturbance
ATPase inactivation
ENERGY CRISIS
16
Nicklas et al., 1985; Ramsay et al., 1986;Mizuno et al., 1987.

17.  This research provided data that progressive loss of MC1 function in dopa neurons trigger progressive and levodopa responsive
parkinsonism which occurred only when somstodendric SNDA fell
 Slow loss of MC1 function caused NDFSU2 deletion caused warberg shift but bioenergetic demands of SN can be met by OXPHOS which
was found to be declined by ageing.
.
https://doi.org/10.1038/s41586-021-04059-010.1038/s41586-021-04059- González-Rodríguez2021 17

18.  A metabolomic analysis of the plasma was made from a mouse model of prodromal PD (p-PD). Increased levels
of isobutyrylcarnitine in p-PD mice show an abnormality in β-oxidation in mitochondria
 Increased levels of pyrimidine nucleoside can be associated with mitochondrial dysfunction. Consistent with
these results, the immunoblot analysis showed a defect in mitochondrial complex I assembly in p-PD mice.
Masashi Ikuno, Hodaka Yamakado, Ikuko Amano, Yusuke Hatanaka, Norihito Uemura, Shu-ichi Matsuzawa, Ryosuke Takahashi,Mitochondrial dysfunction in a mouse model of prodromal Parkinson’s disease: A
metabolomic analysis,Neuroscience Letters,Volume765,2021,136267,ISSN 0304-3940,https://doi.org/10.1016/j.neulet.2021.136267 18

19. https://doi.org/10.1155/2021/557754110.1155/2021/5577541 Oxidative Medicine and Cellular Longevity
 Oxidation of cardiolipin in the substantia nigra is enhanced by rotenone, an inhibitor of complex I, in a model of PD so ,inhibition
of cardiolipin oxidation allows a correct functioning of the mitochondria.
 Adequate levels of cardiolipin are crucial for efficient electron transport between CoQ and complex, maintain normal
mitochondrial cristae structure and correct assembly of the electron chain supercomplexes
 melatonin resulted in a significant reduction of oxidative stress markers. significant increases of catalase, complex I activity, and
respiratory control , prevents cardiolipin loss and oxidation which avoids mitochondrial membrane permeabilization induced by
reactive oxygen species and other factors
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20. THERAPEUTIC
OPTIONS
MPPE
Urso
deoxycholic
acid
metformin
Niacin
MAO-B inhibitor
• Prevents MPTP induced
neural loss by
upregulating Super
oxide dismutase
o Beneficial for treating
LRRK2 mutation
o Protection against toxic
and genetic forms of PD
20
Anne Grünewald, Kishore R. Kumar, Carolyn M. Sue,New insights into the complex role of mitochondria in Parkinson’s disease,Progress in Neurobiology,Volume 177,2019,Pages 73-93,ISSN 0301-
0082,https://doi.org/10.1016/j.pneurobio.2018.09.003.
Decreases the ROS
production at mc1 by
reverse electron
transfer
Binds to
GPR109A
that provide
protection
from MPP+

21. 21
Clinical trial status of some therapies
Clinicaltrials.gov.in

22. CONCLUSION
 So on a final note we can conclude that complex 1 dysfunction undergoes oxidative damage
particularly in NDFSU2 and few subunits of N module lead to a progressive loss of function .
 Warberg shift type of remodeling for decreasing energy requirements.In a metabolomic analysis of
predromic mice increased levels pyridine nucleoside levels found explaining defect in MC1.
 It was also found that cardiolipin level disturbances also causes dysfunction in complex 1 activity there
by contributing to PD.Mutations in genes such as Tfam, LRRK2,PGC1alpha, and external factors such
as MPP ,rotenone also lead to functional dysfunction of Mitochondrial complex 1 causing disturbance
in energitics and increase in ROS that ultimately causing cell death
22

23. REFERENCES
1. Gzálezon-Rodríguez P, Zampese E, Stout KA, Guzman JN, Ilijic E, Yang B, Tkatch T, Stavarache MA, Wokosin DL, Gao L, Kaplitt
MG, López-Barneo J, Schumacker PT, Surmeier DJ. Disruption of mitochondrial complex I induces progressive parkinsonism.
Nature. 2021 Nov;599(7886):650-656. doi: 10.1038/s41586-021-04059-0. Epub 2021 Nov 3. PMID: 34732887.
2. Subrahmanian N, LaVoie MJ. Is there a special relationship between complex I activity and nigral neuronal loss in Parkinson's
disease? A critical reappraisal. Brain Res. 2021 Sep 15;1767:147434. doi: 10.1016/j.brainres.2021.147434. Epub 2021 Mar 19.
PMID: 33745923.
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2728https://doi.org/10.1016/j.bbabio.2016.02.013
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assembly in health and disease Biochimica et Biophysica Acta (BBA) - Bioenergetics,Volume 1817, Issue 6,2012,Pages 851-
862,ISSN 0005-2728,https://doi.org/10.1016/j.bbabio.2011.08.010.
5. Ekstrand MI, Galter D. The MitoPark Mouse - an animal model of Parkinson's disease with impaired respiratory chain function in
dopamine neurons. Parkinsonism Relat Disord. 2009 Dec;15 Suppl 3:S185-8. doi: 10.1016/S1353-8020(09)70811-9. PMID:
20082987.
6. Keeney PM, Xie J, Capaldi RA, Bennett JP Jr. Parkinson's disease brain mitochondrial complex I has oxidatively damaged subunits
and is functionally impaired and misassembled. J Neurosci. 2006 May 10;26(19):5256-64. doi: 10.1523/JNEUROSCI.0984-06.2006.
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