低酸素症と複合体内遺伝抑制剤は,複合体I変異体を共通のメカニズムで救出する

Joshua D Meisel¹, Maria Miranda¹, Owen S Skinner¹

¹Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA; Broad Institute, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, MA 02114, USA.

Cell

|January 12, 2024

まとめ

ミトコンドリアの電子輸送連鎖複合体Iの異常から神経疾患を救済する. この効果はC. elegansに保存され,アクセサリーサブユニットとユビキノン結合ポケットに関連しています.

科学分野:

生物化学
細胞生物学
遺伝学

背景:

電子輸送連鎖 (ETC) は細胞呼吸に不可欠であり,電子の流れと陽子のポンプを結び付けます.
ミトコンドリア複合体I機能不全は神経疾患を引き起こすが,低酸素による救済は十分に理解されていない.
この現象の進化的保存と根本的なメカニズムは未知のままです

研究の目的:

電子輸送連鎖複合体I欠乏症における低酸素誘発による救済の進化的保存と分子メカニズムを調査する.
低酸素状態での複合I機能の回復に関与する遺伝的要因と分子相互作用を特定する.

主な方法:

モデル生物C. elegansを用いて,複合体I欠乏症の低酸素救出と高酸素感受性を研究した.
複合I付属サブユニットNDUFA6/nuo-3の抑制変異を特定するための遺伝子スクリーニングを実施した.
複合I 前進活動,電子輸送鎖の流れ,および複合Iレベルを評価するために生化学的測定を行った.

主要な成果:

複合体I欠乏症の低酸素救出と高酸素感は,C. elegansで進化的に保存されています.
救出は,複合体Iの電子伝導マトリックスアームに影響を与える変異体に特異的です.
NDUFA6/nuo-3フェノコピー低酸素症の抑制変異は,複合体I前方活性を再生することによって救出されます.
ユビキノン結合ポケット内の残留物は,NDUFA6 / nuO-3変異または低酸素による救済に不可欠です.

結論:

HIF経路やROSとは関係なく,前向きな酵素活性を直接回復することによって,複合体I欠乏症を救済します.
コンプレックスIのユビキノン結合ポケットとアクセサリーサブユニット (NDUFA6) の間にある酸素に敏感な結合メカニズムが,この救済の基礎となっている.
この発見は,ミトコンドリア呼吸器の調節と,複雑なI関連疾患の潜在的な治療戦略に関する新しい洞察を提供します.

キーワード:

C. エレガンス NADH:ウビキノン酸化還元酵素 NDUFA6 について NDUFS4 について複合体 I 電子輸送連鎖高酸素症低酸素ミトコンドリア酸素

さらに関連する動画

05:45

Author Spotlight: Unveiling Oxidative Phosphorylation System Dynamics and Mitochondrial Roles in Health and Disease

Published on: May 3, 2024

1.2K

07:55

A Deep-sequencing-assisted, Spontaneous Suppressor Screen in the Fission Yeast Schizosaccharomyces pombe

Published on: March 7, 2019

8.0K

関連する概念動画

01:46

Electron Transport Chain: Complex I and II

13.4K

The mitochondrial electron transport chain (ETC) is the main energy generation system in the eukaryotic cells. However, mitochondria also produce cytotoxic reactive oxygen species (ROS) due to the large electron flow during oxidative phosphorylation. While Complex I is one of the primary sources of superoxide radicals, ROS production by Complex II is uncommon and may only be observed in cancer cells with mutated complexes.
ROS generation is regulated and maintained at moderate levels necessary...

13.4K

01:30

The Electron Transport Chain

16.8K

The electron transport chain or oxidative phosphorylation is an exothermic process in which free energy released during electron transfer reactions is coupled to ATP synthesis. This process is a significant source of energy in aerobic cells, and therefore inhibitors of the electron transport chain can be detrimental to the cell's metabolic processes.
Inhibitors of the electron transport chain
Rotenone, a widely used pesticide, prevents electron transfer from Fe-S cluster to ubiquinone or Q...

16.8K

01:43

Electron Transport Chain: Complex III and IV

7.5K

During the electron transport chain, electrons from NADH and FADH2 are first transferred to complexes I and II, respectively. These two complexes then transfer the electrons to ubiquinol, which carries them further to complex III. Complex III passes the electrons across the intermembrane space to Cyt c, which carries them further to complex IV. Complex IV donates electrons to oxygen and reduces it to water. As electrons pass through complexes I, III, and IV, the energy released aids the pumping...

7.5K

01:41

The Supercomplexes in the Crista Membrane

2.5K

The mitochondrial cristae membrane is the primary site for the oxidative phosphorylation (OXPHOS) process of energy conversion mediated through respiratory complexes I to V. These complexes have been widely studied for decades, and it has been proven that they form supramolecular structures called respiratory supercomplexes (SC). These higher-order complexes may be crucial in maintaining the biochemical structure and improving the physiological activity of the individual complexes while...

2.5K

01:48

ATP Synthase: Mechanism

14.6K

In animals, the mitochondrial F1F0 ATP synthase is the key protein that synthesizes ATP molecules through a complex catalytic mechanism. While the nuclear genome encodes the majority of ATP synthase subunits, the mitochondrial genome encodes some of the enzyme's most critical components. The formation of this multi-subunit enzyme is a complex multi-step process regulated at the level of transcription, translation, and assembly. Defects in one or more of these steps can result in decreased...

14.6K

02:59

Animal Mitochondrial Genetics

7.6K

Among all the organelles in an animal cell, only mitochondria have their own independent genomes. Animal mitochondrial DNA is a double-stranded, closed-circular molecule with around 20,000 base pairs. Mitochondrial DNA is unique in that one of its two strands, the heavy, or H, -strand is guanine rich, whereas the complementary strand is cytosine rich and called the light, or L, -strand. Compared to nuclear DNA, mitochondrial DNA has a very low percentage of non-coding regions and is marked by...