БИОХИМИЯ, 2022, том 87, вып. 2, с. 289–304

УДК 577.24;577.217;577.25

В фокусе молекулярные функции антивозрастной деацетилазы SIRT3

© 2022 J. Nahálkovájarmila.nahalkova@biochemworld.net

Biochemistry, Molecular, and Cell Biology Unit, Biochemworld Co., 74394 Skyttorp, Uppsala County, Sweden

Поступила в редакцию 11.11.2021
После доработки 20.12.2021
Принята к публикации 22.12.2021

DOI: 10.31857/S0320972522020105

КЛЮЧЕВЫЕ СЛОВА: SIRT3, NAD+-зависимая деацетилаза, сеть белковых взаимодействий, анализ обогащения путей, старение, дыхательная цепь транспорта электронов, митохондрии, возрастные заболевания.

Аннотация

Белок сиртуин 3 (SIRT3) представляет собой лизиндеацетилазу, играющую важную роль в поддержании целостности митохондрий, являющихся уязвимой мишенью при многих заболеваниях. Интересно, что клеточное старение может быть обращено только лишь путём суперэкспрессии SIRT3, что вызывает много вопросов о роли SIRT3 в молекулярных механизмах борьбы со старением. Анализ функционирования SIRT3 мы провели на основе имеющихся данных по взаимодействию 407 субстратов этого белка. Результаты изучения многообразия путей и прогнозирования функций генов подтвердили роль SIRT3 в первичном метаболизме и производстве ATP митохондриями. Кроме того, SIRT3, предположительно, задействован в термогенезе, при развитии дегенеративных заболеваний головного мозга, таких как болезнь Альцгеймера, болезнь Паркинсона, болезнь Хантингтона, а также неалкогольной жировой болезни печени. Приоритизация белков в узлах исследуемого пути продемонстрировала, что субъединицы комплекса I дыхательной цепи митохондрий (MRC) являются основными регуляторными точками во всей сети взаимодействий. Дополнительными приоритетными узлами оказались субъединица сукцинатдегидрогеназы B (SDHB) комплекса II и ATP5F1 комплекса V MRC. Проведенный анализ подтверждает существование NADH/NAD+-зависимой регуляторной петли обратной связи между SIRT3, комплексом I MRC и ацетил-КоА-синтетазами, а также наличие ядерных субстратов SIRT3. Малоисследованные функции субстратов SIRT3, таких как LMNA и LMNB, HIF‑1α, p53, DNA‑PK и PARK7, отмечены как перспективные для дальнейших научных исследований. SIRT3 действует как репрессор BACE1 через SIRT3-LKB1-AMPK-CREB-PGC1A-PPARG-BACE1 (SIRT3-BACE1), функции которого наилучшим образом соответствуют механизмам циркадного ритма. Формируется новая рабочая гипотеза терапевтической мишени для лечения болезни Альцгеймера. Также обозначены другие важные пути терапевтических вмешательств, ассоциированные с активностью SIRT3.

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Благодарности

Исследование было выполнено при поддержке Biochemworld Co., округ Уппсала, Швеция.

Конфликт интересов

Автор заявляет об отсутствии конфликта интересов.

Соблюдение этических норм

Настоящая статья не содержит описания каких-либо исследований с участием людей или животных в качестве объектов.

Дополнительные материалы

Приложение к статье на английском языке опубликовано на сайте журнала «Biochemistry» (Moscow) (http://protein.bio.msu.ru/biokhimiya/) и на сайте издательства Springer (www.springer.com/journal/10541), том 87, вып. 1, 2022.

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