TUGAS MATA KULIAH UMUM BAHASA INGGRIS

NEW VOCABULARIES AND SHORT SUMMARY ABOUT

MEDICINAL SCIENCE JOURNAL

Dosen Pengampu:

Dr. Wisma Yunita, M.Pd

Disusun Oleh:

Fajar Cristianta Ginting (H1A022014)

PROGRAM STUDI PENDIDIKAN DOKTER

FAKULTAS KEDOKTERAN DAN ILMU KESEHATAN

UNIVERSITAS BENGKULU
2022
 Mitochondrial permeability
transition and oxidative stress
A. Abstract
Mitochondrial permeability transition (MPT) is non-selective inner membrane
permeabilization that may precede necrotic and apoptotic cell death. Although this
process has a specific inhibitor, cyclosporin A, little is known about the nature of the
proteinaceous pore that results in MPT. Here, we review data indicating that MPT is not a
consequence of the opening of a pre-formed pore, but the consequence of oxidative
damage to pre-existing membrane proteins.

B. Keywords
 Mitochondrion
 Calcium
 Reactive oxygen
 Free radical
 Thiol
 Cell death

C. Abbreviations
 GPx, Glutathione Peroxidase;
 GSH, Glutathione;
 MPT, mitochondrial permeability transition;
 Pi, Inorganic Phosphate;
 ROS, Reactive Oxygen Species;
 TPx, Thioredoxin peroxidase;
 TSH, Thioredoxin.

D. Introduction
After the discovery that mitochondrial components, including the apoptosis-inducing
factor and cytochrome c, can trigger apoptosis, attention has concentrated on mechanisms
through which mitochondria control cell death. One of the many processes that allow
mitochondria to release apoptogenic signal molecules into the cytosol is the occurrence of
mitochondrial permeability transition (MPT). MPT is non-selective permeabilization of
the inner mitochondrial membrane typically promoted by the accumulation of excessive
quantities of Ca2+ ions and stimulated by a variety of compounds or conditions. The
inner membrane permeabilization caused by MPT results in loss of matrix components,
impairment of mitochondrial functionality, and substantial swelling of the organelle, with
consequent outer membrane rupture and cytochrome c release.
Despite extensive research, the exact nature of the membrane alterations that lead to MPT
remains unanswered. Since MPT is a partially reversible process mediated by membrane
protein thiol oxidation and inhibited by cyclosporin A, it involves membrane proteins.
However, no novel inner membrane pore to date has shown MPT characteristics. Instead,
MPT is almost certainly caused by a group of modified and assembled inner and outer
membrane components [9], including the ADP/ATP translocator, cyclophilin D, and,
possibly, porin and hexokinase.
Another uncertainty involving MPT is the mechanism through which normal components
of mitochondria that participate in MPT assemble to form a non-selective pore upon
excessive accumulation of Ca2+. In this article, we review data that strongly suggest that
the link between excessive mitochondrial Ca2+ accumulation and MPT is oxidative
stress.

E. MPT can be induced by mitochondrial pyridine

nucleotide oxidation
Early experiments involving ruthenium red-insensitive mitochondrial Ca2+ release (now
attributable to MPT) showed that this process could be stimulated by promoting the
oxidation of mitochondrial pyridine nucleotides, and inhibited or reversed by NAD(P)+
reduction. Subsequent data confirmed that NAD(P) redox status, manipulated through the
use of reductants and oxidants, regulated the onset of MPT. In addition, oxidation of
NADPH was shown to be more closely linked to MPT than that of NADH. These
findings were the first indication that MPT was related to the redox state of mitochondria
and could be caused by reactive oxygen species (ROS) since NADPH plays a central role
in mitochondrial defense against oxidative stress. The reductive effect of NADPH on
glutathione (GSH) and thioredoxin (TSH), which are substrates for mitochondrial
glutathione peroxidase (GPx) and thioredoxin peroxidase (TPx), maintains the
functionality of the main H2O2 removal enzymes in the organelle. Moreover, in the
absence of adequate superoxide (O2radical dot−) removal, further oxidation of NAD(P)H
could be caused by aconitase inhibition, intensifying mitochondrial oxidative stress.
An interesting substantiation of the link between MPT and the NAD(P) redox state is the
effect of the membrane potential in this process. As long as intramitochondrial Ca2+
stores are maintained high, large decreases in transmembrane electrical potential
stimulate MPT. Increased transmembrane electrical potentials, such as those observed in
cells overexpressing the anti-apoptotic protein Bcl-2, prevent MPT. This regulation of
MPT is most probably mediated by the effects of membrane potential changes on the
NAD(P) redox status, as controlled by the membrane potential-sensitive NADP
transhydrogenase.
The indirect antioxidant effect of the energy-linked NADP transhydrogenase may be an
evolutionary defense against oxidative stress since high membrane potentials favor ROS
generation. High membrane potentials are accompanied by slower respiratory rates,
which stimulate ROS generation by increasing O2 tension in the tissues and favoring
longer life spans of highly reactive intermediates of the electron transfer chain such as
semiquinone radicals. Thus, ideal protection against oxidative stress should be obtained
under conditions of mild uncoupling (lowering the membrane potential by ≈15 mV),
when the reaction catalyzed by the NADP transhydrogenase is still shifted toward
generating NADPH, but ROS generation is largely diminished.

F. MPT is promoted by thiol oxidation

Since NAD(P)H redox status is intimately associated with GSH and mitochondrial
protein thiol redox state, it is logical to suppose that MPT is related to membrane protein
thiol status. Indeed, MPT is prevented by thiol reductants such as dithiothreitol, while
thiol oxidants such as diamide, phenyl arsine oxide, and 4,4′-diisothiocyanato-stilbene-
2,2′-sulfonic acid promote MPT. Thiol oxidants and reductants may regulate MPT both
by controlling mitochondrial GSH levels or by direct changes in the redox state of MPT
pore thiols. Interestingly, Costantini et al, have shown that two distinct membrane thiol
pools regulate the opening of the MPT pore, each with reactivity toward distinct thiol
reagents.
Thus, we now know that MPT occurs when thiol groups of inner membrane proteins are
oxidized, resulting in conformational changes that, somehow, form a large non-selective
pore. Interestingly, thiol cross-linkage seems to be essential for these conformational
changes, since only dithiol reagents promote MPT. Indeed, cross-linked inner membrane
proteins can be observed after MPT on sodium dodecyl sulfate-polyacrylamide gel
electrophoresis of solubilized membrane proteins, The proteins which must be cross-
linked to result in MPT have still not been determined, but most certainly involve the
ADP/ATP translocator. In this regard, Vercesi showed evidence for the participation of
the ADP/ATP translocator and membrane protein thiol oxidation in the mechanism of
NADP+-stimulated Ca2+ release from mitochondria. In addition, a critical cysteine
residue (Cys56) of the ADP/ATP translocator is oxidized in isolated mitochondria and
cells which underwent MPT.

G. MPT is inhibited by antioxidants

Based on the evidence that MPT was stimulated by thiol oxidation and depletion of
mitochondrial NADPH, we decided to directly test the hypothesis that MPT was caused
by oxidative stress. Confirming our initial proposition, we observed that a wide variety of
antioxidants protect against MPT. The finding that catalase and thiol peroxidases protect
against MPT was especially significant since it indicates that MPT can be induced
directly by ROS, and depends on the presence of H2O2. Mitochondrial H2O2 derives
from superoxide radicals (see Fig. 1) and is converted to hydroxyl radicals, via the Fe2+-
dependent Fenton reaction, before promoting MPT.

Fig. 1. Mitochondrial ROS accumulation causes MPT. The respiratory chain, inserted in
the inner mitochondrial membrane, constantly generates small quantities of superoxide
radicals (O2radical dot−). These radicals are normally removed by Mn-superoxide
dismutase (MnSOD), which promotes the generation of H2O2. H2O2 is then reduced to
water by GPx, TPx, or catalase (in heart mitochondria). GSH, oxidized by GPx, and TSH,
oxidized by TPx, are recovered by glutathione and thioredoxin reductases (GR and TR),
which use NADPH as an electron donor. NADH, which is available in quantities
regulated by respiration and Bcl-2, then reduces NADP+, using the NADP
transhydrogenase (TH). When O2radical dot− generation increases in the presence of
Ca2+ and Pi, and/or H2O2 removal pathways are inactivated, H2O2 accumulates in
quantities too large for removal, and, in the presence of Fe2+, generates the highly
reactive HOradical dot radical. radical dot oxidizes thiol (–SH) groups of the MPT pore
complex, leading to pore assembly and opening. Alternatively, the HOradical dot may
also promote membrane permeabilization through lipid oxidation, a process strongly
stimulated by Pi.
The obvious source of ROS production leading to MPT is the mitochondrial respiratory
chain. We have determined that the semiquinone form of coenzyme Q is a significant
generator of superoxide radicals that ultimately promote MPT, and that a decrease in the
concentration of molecular oxygen in the reaction medium protects against MPT.
Although the pronounced inhibition of MPT in anaerobiosis supports the participation of
ROS in MPT, it is important to stress that free radicals may be formed through electron
donation to components of the mitochondrial suspension even in the absence of oxygen.
These free radicals could be responsible for MPT observed under anaerobic conditions.
However, we have also shown that full removal of molecular oxygen from the
mitochondrial suspension is not easily obtained, explaining why ROS may be present
under apparent anaerobiosis. In the full absence of ROS, MPT appears to be fully
inhibited when promoted by Ca2+ and inorganic phosphate (Pi) or NAD(P)H oxidants,
but may still be promoted by direct oxidation of inner membrane protein thiols using thiol
reagents.
Further evidence that MPT was caused by ROS was provided by the discovery that this
process could be promoted through the addition of exogenous sources of ROS. Nitrogen-
containing ROS such as peroxynitrite cause protein thiol oxidation and MPT, paralleled
by membrane lipid oxidation.

H. Ca2+ and Pi lead to mitochondrial oxidative stress

Protection against MPT conferred by antioxidants such as catalase is observed not only
when MPT is caused by NAD(P)H oxidation, but also when MPT is induced by Ca2+
and Pi in the absence of NAD(P)H oxidants. This finding suggests that Ca2+ and Pi can,
alone, lead to a condition of oxidative stress in mitochondria. Indeed, we measured a
large increase in ROS generation when mitochondria were treated with Ca2+ and Pi. To
date, there is no clear understanding of why Pi, despite decreasing matrix-free Ca2+
concentrations, increases ROS generation and stimulates MPT. Pi may catalyze reactions
that favor ROS formation.
Grijalba et al have developed an interesting hypothesis, supported by experimental data,
to explain how Ca2+ may increase mitochondrial ROS formation. They demonstrated
that Ca2+ alters the lipid organization of the inner mitochondrial membrane by
interacting with the anionic head of cardiolipin, an abundant component of this
membrane. These alterations in membrane organization may affect respiratory chain
function, including coenzyme Q mobility, and favor monoelectronic oxygen reduction
(superoxide radical generation) at intermediate steps of the respiratory chain.

G. MPT can be associated with other forms of

mitochondrial oxidative damage
Further evidence for the role of oxidative stress in MPT is the associated occurrence of
oxidative damage to non-protein mitochondrial components. Extensive lipid oxidation
parallels MPT when mitochondria are treated with high phosphate concentrations. Pi
stimulates lipid oxidation due to its ability to catalyze aldehyde tautomerization
producing enols, which, when oxidized by heme proteins, yield triplet state aldehydes
that are ROS themselves. Lipid oxidation is also associated with MPT promoted by
peroxynitrite. Lipid oxidation may increase the destructive effects of MPT in cells since it
also promotes mitochondrial swelling, cytochrome c release, and impaired oxidative
phosphorylation. Indeed, the short-term irreversibility of membrane lipid oxidation
makes this form of mitochondrial damage potentially more lethal than MPT, which is
reversible soon after its onset.

H. In situ MPT is related to the cellular redox state

While most of our data relating MPT to mitochondrial oxidative stress was collected
from isolated organelle studies, a large number of experiments using intact cells now
support our conclusions. Cell death under conditions that may involve MPT can be
prevented by antioxidants, while NAD(P)H oxidants promote mitochondrial oxidative
stress and MPT in intact cells. In addition, reduced GSH, which prevents MPT, has been
shown to promote cell survival after injurious stimuli.
MPT occurring inside cells may be a manner of eliminating individual mitochondria
(‘mitoptosis’) which produce excessive ROS. Thus, MPT may be a last-line cellular
defense mechanism against mitochondrially generated ROS.

K. Short Summary
This Journal Mediicine Science explain about data indicating that MPT is not a
consequence of the opening of a pre-formed pore, but the consequence of oxidative
damage to pre-existing membrane proteins. While most of our data relating MPT to
mitochondrial oxidative stress was collected from isolated organelle studies, a large
number of experiments using intact cells now support our conclusions.
Cell death under conditions that may involve MPT can be prevented by antioxidants,
while NAD(P)H oxidants promote mitochondrial oxidative stress and MPT in intact cells.
In addition, reduced GSH, which prevents MPT, has been shown to promote cell survival
after injurious stimuli. MPT occurring inside cells may be a manner of eliminating
individual mitochondria (‘mitoptosis’) which produce excessive ROS. Thus, MPT may
be a last-line cellular defense mechanism against mitochondrially generated ROS.

L. Vocabulary Meanings
No Vocabulary Meanings
.
1 Mitochondrio Mitokondria, organel terikat membran yang ditemukan dalam
n sitoplasma hampir semua sel eukariotik (sel dengan inti yang
 jelas), fungsi utamanya adalah untuk menghasilkan sejumlah
besar energi dalam bentuk adenosin trifosfat (ATP). Mitokondria
biasanya berbentuk bulat hingga oval dan ukurannya berkisar
antara 0,5 hingga 10 μm. Selain menghasilkan energi,
mitokondria menyimpan kalsium untuk aktivitas pensinyalan
sel, menghasilkan panas, dan memediasi pertumbuhan dan
kematian sel.
2 Calcium Unsur kimia logam dari kelompok alkali-bumi yang terjadi
secara alami hanya dalam kombinasi dan sangat penting untuk
fungsi seluler di semua organisme yang dikenal.
3 ROS, Spesies oksigen reaktif (ROS) adalah bahan kimia yang sangat
Reactive reaktif yang terbentuk dari O2. Contoh ROS termasuk peroksida,
oxygen superoksida, radikal hidroksil, oksigen singlet,[1] dan alfa-
Species oksigen. Dalam konteks biologis, ROS adalah produk sampingan
dari metabolisme oksigen normal. ROS memiliki peran dalam
pensinyalan sel dan homeostasis.
ROS bersifat intrinsik terhadap fungsi seluler dan hadir pada
tingkat rendah dan stasioner dalam sel normal. Pada tanaman,
ROS terlibat dalam proses metabolisme yang berkaitan dengan
photoprotection dan toleransi terhadap berbagai jenis
stres. Namun, ROS dapat menyebabkan kerusakan permanen
pada DNA karena mereka mengoksidasi dan memodifikasi
beberapa komponen seluler dan mencegah mereka melakukan
fungsi aslinya.
Ini menunjukkan bahwa ROS memiliki peran ganda; apakah
mereka akan bertindak sebagai faktor berbahaya, protektif, atau
pensinyalan tergantung pada keseimbangan antara produksi dan
pembuangan ROS pada waktu dan tempat yang tepat. Dengan
kata lain, toksisitas oksigen dapat muncul baik dari produksi
yang tidak terkontrol maupun dari eliminasi ROS yang tidak
efisien oleh sistem antioksidan.
Selama masa stres lingkungan (misalnya, UV atau paparan
panas), kadar ROS dapat meningkat secara dramatis. [4] Hal ini
dapat mengakibatkan kerusakan signifikan pada struktur
sel. Secara kumulatif, ini dikenal sebagai stres oksidatif.
Produksi ROS sangat dipengaruhi oleh respons faktor stres pada
tanaman, faktor-faktor yang meningkatkan produksi ROS ini
meliputi kekeringan, salinitas, kedinginan, pertahanan patogen,
kekurangan nutrisi, toksisitas logam, dan radiasi UV-B. ROS
juga dihasilkan oleh sumber eksogen seperti radiasi pengion
yang menghasilkan efek ireversibel dalam pengembangan
jaringan pada hewan dan tumbuhan.
4 Free radical Jenis molekul tidak stabil yang dibuat selama metabolisme sel
normal (perubahan kimia yang terjadi dalam sel). Radikal bebas
dapat menumpuk di dalam sel dan menyebabkan kerusakan
pada molekul lain, seperti DNA, lipid, dan protein.
5 Thiol Turunan tiol adalah senyawa organosulfur dari bentuk R−SH, di
mana R mewakili alkil atau substituen organik lainnya. Gugus
fungsi –SH sendiri disebut sebagai gugus tiol atau gugus
sulfhidril, atau gugus sulfanil. Tiol adalah analog sulfur alkohol
(yaitu, belerang menggantikan oksigen dalam gugus hidroksil
alkohol), dan kata tersebut adalah campuran dari "thio-" dengan
"alkohol", di mana kata pertama yang berasal dari bahasa Yunani
θεῖον (theion) yang berarti "belerang".
6 Cell death Jika sel tidak lagi diperlukan, mereka bunuh diri dengan
mengaktifkan program kematian intraseluler. Oleh karena itu,
proses ini disebut kematian sel terprogram, meskipun lebih
sering disebut apoptosis (dari kata Yunani yang berarti "jatuh,"
sebagai daun dari pohon).
7 GPx, Glutathione Peroxidase (GPx) adalah enzim sitosolik yang
Glutathione mengkatalisis reduksi hidrogen peroksida menjadi air dan
Peroxidase oksigen serta mengkatalisasi reduksi radikal peroksida menjadi
alkohol dan oksigen.
8 GSH, Peptida C10H17N3O6S yang mengandung satu residu asam
Glutathione amino masing-masing asam glutamat, Sistein, dan glisin, yang
terjadi secara luas di jaringan tumbuhan dan hewan, dan yang
memainkan peran penting dalam proses oksidasi-reduksi biologis
dan sebagai koenzim.
9 MPT, Pori transisi permeabilitas mitokondria (mPTP atau MPTP; juga
Mitochondrial disebut sebagai PTP, mTP, atau MTP) adalah protein yang
Permeability terbentuk di membran bagian dalam mitokondria dalam kondisi
Transition patologis tertentu seperti cedera otak traumatis dan stroke.
Pembukaan memungkinkan peningkatan permeabilitas membran
mitokondria ke molekul kurang dari 1500 Dalton dalam berat
molekul. Induksi pori transisi permeabilitas, transisi
permeabilitas membran mitokondria (mTP atau MPT), dapat
menyebabkan pembengkakan mitokondria dan kematian sel
melalui apoptosis atau nekrosis tergantung pada pengaturan
biologis tertentu.
10 Pi, Inorganic Fosfat anorganik (Pi) adalah nutrisi penting bagi organisme
Phosphate hidup. Ini memainkan peran kunci dalam proses biologis yang
beragam, termasuk diferensiasi osteoblas dan mineralisasi
kerangka.
 11 TPx, Ekspresi thioredoxin peroksidase tikus dalam PC 12 sel
Thioredoxin pheochromocytoma memperpanjang kelangsungan hidup sel
peroxidase tanpa adanya faktor pertumbuhan saraf dan serum, menunjukkan
bahwa thioredoxin peroksidase dapat meningkatkan
kelangsungan hidup sel saraf.
12 TSH/TRX, Thioredoxin (TRX) memainkan peran sitoprotektif terhadap
Thioredoxin berbagai tekanan oksidatif dalam berbagai sistem.27 Thioredoxin
memiliki aktivitas pemulungan radikal. Thioredoxin dapat
melindungi sel dari faktor nekrosis tumor (TNF) atau antibodi
anti-Fas, hidrogen peroksida, neutrofil aktif, dan cedera reperfusi
iskemik. TRX dapat secara efektif mengurangi ikatan disulfida
protein yang larut dalam lensa yang dihasilkan oleh H2O2 dan
bertindak sebagai quencher radikal bebas.

M. Acknowledgments
Supported by CNPq and FAPESP grants to A.J.K., R.F.C., and A.E.V.

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TUGAS MATA KULIAH UMUM BAHASA INGGRIS

NEW VOCABULARIES AND SHORT SUMMARY ABOUT

MEDICINAL SCIENCE JOURNAL

Dosen Pengampu:

Dr. Wisma Yunita, M.Pd

 Disusun Oleh:

Fajar Cristianta Ginting (H1A 022014)

PROGRAM STUDI PENDIDIKAN DOKTER

FAKULTAS KEDOKTERAN DAN ILMU KESEHATAN

UNIVERSITAS BENGKULU
2022