Mitochondria, the double-membrane semi-autonomous organelles, occupy a pivotal role in cellular energy production, serving as the primary hub for aerobic respiration and ATP synthesis. Their vitality within cells is evident, with their functional status intricately linked to diverse factors, including mitochondrial membrane potential, membrane channels, calcium concentration, respiratory chain complex activity, reactive oxygen species (ROS) generation, and DNA integrity.
In order to maintain the integrity and function of mitochondria, cells perform mitochondrial quality control through various methods such as mitophagy. Mitophagy is an important mechanism that functions when cells are exposed to stress conditions such as reactive oxygen species, which lead to the progressive accumulation of mitochondrial DNA mutations, reduction in mitochondrial membrane potential, and depolarization damage, which may ultimately lead to cell death.
Mitophagy encompasses a sequence of key events: depolarization of impaired mitochondria, encapsulation of these mitochondria by autophagosomes to form mitophagosomes, fusion of mitophagosomes with lysosomes, and the ensuing degradation of mitochondrial contents within lysosomes. This orchestrated process effectively rids the cell of compromised mitochondria, preserving overall cellular health.
Fig.1 Overview of mitophagy (Onishi M., et al. 2021).
The Mechanism of Mitophagy
The mechanisms underpinning mitophagy are primarily categorized into two pathways: ubiquitin-dependent and non-ubiquitin-dependent. The ubiquitin-dependent pathway revolves around the extensive ubiquitination of mitochondrial surface proteins to propel mitophagic events. Among these mechanisms, the PINK1/Parkin pathway stands as one of the most scrutinized. In this pathway, when the mitochondrial membrane potential is compromised, PINK1 accumulates steadfastly on the outer mitochondrial membrane, subsequently recruiting and activating Parkin to initiate the ubiquitination of mitochondrial proteins. This concerted action, in tandem with other ubiquitin-dependent pathways independent of Parkin, orchestrates mitophagy, ensuring the efficient elimination of mitochondria.
In addition, there are non-ubiquitin-dependent pathways that do not rely on ubiquitination but initiate mitophagy through the interaction of proteins on the outer mitochondrial membrane with LC3.
Mitophagy-related Diseases
Uninterrupted mitochondrial function is imperative for cell survival, and the timely removal of damaged mitochondria represents a vital self-preservation mechanism. Interruptions in mitophagy can precipitate a spectrum of maladies, encompassing neurodegenerative and cardiovascular diseases. For instance, mitochondrial dysfunction constitutes a pivotal common denominator in neurodegenerative disorders such as Alzheimer's, Parkinson's, and Huntington's diseases. Familial Parkinson's disease is notably associated with loss-of-function mutations in PINK1 and Parkin. Furthermore, the vigor of cardiomyocytes heavily hinges on mitochondrial energy supply, and impairment in mitochondrial phagocytosis can instigate cardiovascular conditions like cardiac hypertrophy, arrhythmia, and sudden cardiac death.
Detection of Mitophagy
To study mitophagy, researchers continuously advance and refine an array of investigative techniques. These methodologies encompass the examination of mitochondrial morphology, measurement of ROS levels, immunolocalization of autophagosomes and mitochondria, western blot analysis for mitophagy markers, and more. Among these, assessments utilizing mtKeima and mitophagy markers like PINK1, Parkin, BNIP3, NIX, and FUNDC1 are routinely employed.
In summary, mitophagy stands as an indispensable mechanism for preserving cellular health and function, safeguarding against the onset of diverse afflictions. The scientific community perseveres in its diligent exploration of the intricate mechanisms and detection modalities associated with mitophagy, thereby enriching our comprehension of this process and fostering the development of pertinent therapeutic interventions. The continued pursuit of knowledge in this domain holds immense potential for groundbreaking advancements in biomedical research and clinical applications.
References
- Tolkovsky A.M. Mitophagy. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research. 2009, 1793(9): 1508-15.
- Onishi M., et al. Molecular mechanisms and physiological functions of mitophagy. The EMBO Journal. 2021, 40(3):e104705.
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