Mitochondrial Dysfunction Induced by Hyperglycemia as a Key Mechanism in Metabolic Disorders

Abstract

Background: Hyperglycemia is a major feature of metabolic disorders and is closely associated with mitochondrial dysfunction through oxidative stress, impaired bioenergetics, and altered mitochondrial regulation. Plant-derived bioactive compounds have also attracted interest for their potential to modulate these mitochondrial and redox pathways.

Objectives: This review aimed to synthesize published evidence on hyperglycemia-induced mitochondrial dysfunction as a central mechanism in metabolic disorders and to summarize the potential role of plant-derived compounds in modulating mitochondrial pathways.

Methods: This study was conducted as a narrative literature review. Articles were searched through PubMed, SAGE Journals, and ScienceDirect databases for publications from 2015 to 2025. The search terms included combinations of hyperglycemia, mitochondrial dysfunction, oxidative stress, PGC-1α, Nrf2, mitochondrial biogenesis, mitochondrial dynamics, metabolic disorders, and plant-derived extracts. Eligible articles included original studies and review papers discussing mitochondrial alterations under hyperglycemic conditions in in vitro, animal, or human studies. The data were synthesized qualitatively and organized into thematic categories without meta-analysis.

Discussion: Hyperglycemia increases reactive oxygen species (ROS) production, impairs electron transport chain efficiency, and reduces adenosine triphosphate (ATP) generation. It may also disturb mitochondrial quality control by promoting excessive fission and suppressing PGC-1α-mediated mitochondrial biogenesis. Oxidative stress–responsive pathways, including Nrf2, contribute to mitochondrial redox homeostasis under metabolic stress. Polyphenols, flavonoids, and curcumin may modulate these pathways by activating Nrf2-dependent antioxidant responses and supporting mitochondrial biogenesis-related signaling.

Conclusion: Hyperglycemia contributes to mitochondrial dysfunction through oxidative stress, impaired energy metabolism, and altered mitochondrial regulatory pathways. Plant-derived compounds may offer potential protective effects, although many studies remain limited by the lack of direct mitochondrial functional assessment.

Keyword: hyperglycemia; mitochondrial dysfunction; Nrf2; oxidative stress; PGC-1α

Latar Belakang: Hiperglikemia merupakan ciri utama gangguan metabolik dan berhubungan erat dengan disfungsi mitokondria melalui stres oksidatif, gangguan bioenergetika, dan perubahan regulasi mitokondria. Senyawa bioaktif berbasis tanaman juga mendapat perhatian karena berpotensi memodulasi jalur mitokondria dan redoks tersebut. Tujuan: Tinjauan ini bertujuan untuk menyintesis bukti ilmiah mengenai disfungsi mitokondria akibat hiperglikemia sebagai mekanisme penting pada gangguan metabolik, serta merangkum potensi senyawa berbasis tanaman dalam memodulasi jalur mitokondria. Metode: Studi ini disusun sebagai narrative literature review. Penelusuran artikel dilakukan melalui basis data PubMed, SAGE Journals, dan ScienceDirect untuk publikasi tahun 2015 hingga 2025. Kata kunci yang digunakan mencakup kombinasi hyperglycemia, mitochondrial dysfunction, oxidative stress, PGC-1α, Nrf2, mitochondrial biogenesis, mitochondrial dynamics, metabolic disorders, dan plant-derived extracts. Artikel yang memenuhi kriteria meliputi penelitian asli dan artikel review yang membahas perubahan mitokondria pada kondisi hiperglikemia berdasarkan studi in vitro, hewan coba, maupun manusia. Data disintesis secara kualitatif dan disusun dalam kategori tematik tanpa meta-analisis. Pembahasan: Hiperglikemia meningkatkan produksi reactive oxygen species (ROS), menurunkan efisiensi rantai transpor elektron, dan mengurangi pembentukan adenosine triphosphate (ATP). Kondisi ini juga dapat mengganggu kontrol kualitas mitokondria dengan meningkatkan fisi berlebihan dan menekan biogenesis mitokondria yang dimediasi PGC-1α. Jalur respons stres oksidatif, termasuk Nrf2, berperan dalam menjaga homeostasis redoks mitokondria selama stres metabolik. Senyawa fitokimia seperti polifenol, flavonoid, dan kurkumin berpotensi memodulasi jalur tersebut melalui aktivasi respons antioksidan bergantung Nrf2 dan dukungan terhadap regulasi biogenesis mitokondria. Kesimpulan: Hiperglikemia berkontribusi terhadap disfungsi mitokondria melalui stres oksidatif, gangguan metabolisme energi, dan perubahan jalur regulasi mitokondria. Senyawa berbasis tanaman berpotensi memberikan efek protektif, meskipun banyak studi masih terbatas karena belum mengevaluasi fungsi mitokondria secara langsung.

Kata kunci: disfungsi mitokondria; hiperglikemia; Nrf2; PGC-1α; stres oksidatif