Mitochondrial Quality Control: Mechanisms of Biogenesis, Dynamics, and Degradation
Mitochondrial biogenesis
Mitochondrial quality control (MQC) is a comprehensive network that monitors mitochondrial quality and serves as an endogenous protective program, which is crucial for maintaining mitochondrial homeostasis and function [1]. MQC coordinates various processes, such as biogenesis, mitochondrial fission, fusion, mitochondrial protein degradation, and mitophagy, to collectively regulate and maintain mitochondrial homeostasis [2].
Typically, after a period of operation, mitochondrial function begins to decline, prompting fusion between mitochondria to share a common internal system, thereby sustaining normal mitochondrial function. Soon after, if mitochondrial function continues to degrade, the mitochondria will start to undergo fission to eliminate damaged ones. Healthy mitochondria will continue to fuse, while the eliminated ones will be degraded and recycled through autophagy. Mitochondrial fission, fusion, and autophagy are all aimed at enhancing the mitochondria's ability to perform their tasks: mitochondrial biogenesis (Figure 1).
Mitochondrial biogenesis is a regeneration program that maintains mitochondrial quantity by replacing old and damaged mitochondria with new and healthy ones. This process is regulated by both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA), involving multiple transcription factors [3]. The newly generated mitochondria from biogenesis can promote ATP production to meet metabolic demands under physiological (such as exercise and cold) and pathological (such as diabetic ischemic cardiomyopathy and ischemic heart disease) conditions [4].
Mitochondrial dynamics
Mitochondria are highly dynamic organelles capable of continuous cycles of fusion and fission, which alter their morphology, size, and location; this physiological process is known as mitochondrial dynamics [4].
Fusion is typically a defensive response, where two mitochondria can merge their inner and outer membranes to form a single tubular mitochondrion, thereby enhancing the resilience of the mitochondrial network (Figure 2) [1]. Mitochondrial fusion is induced by the homotypic and heterotypic interactions between mitochondrial outer membrane (OMM) proteins, mitofusin 1 and 2 (Mfn1/2), and optic atrophy protein 1 (OPA1) located in the inner mitochondrial membrane (IMM). Mitochondrial fusion can facilitate the exchange of mtDNA, membrane phospholipids, and respiratory-related proteins, as well as intermediates of the tricarboxylic acid (TCA) cycle. Therefore, the newly formed organelles possess heterogeneous membrane potentials and a diverse pool of proteins, metabolites, and mtDNA [4].
In contrast, mitochondrial fission fragments the tubular mitochondrial network into smaller organelles, which aids in the elimination of depolarized mitochondria through mitophagy.
Mitochondrial fission mainly occurs in three steps: 1. Phosphorylation (activation) of dynamin-related protein 1 (Drp1); 2. Recruitment of Drp1 to the OMM through interactions with Drp1 receptors, including fission protein 1 (Fis1), mitochondrial fission factor (Mff), and mitochondrial dynamics proteins (MiD49 and MiD51); 3. Assembly of Drp1 into a ring structure that encircles and constricts the mitochondrion, consuming GTP to produce two separate organelles (Figure 3). This process not only meets the increased energy demands of the cell but also separates low membrane potential damaged mitochondrial components from the overall mitochondrial network to maintain mitochondrial health [4].
Under physiological conditions, mitochondrial fusion and fission counterbalance each other, achieving a certain dynamic equilibrium. Once this balance is disrupted—when mitochondrial fusion and fission are impaired—it can lead to mitochondrial dysfunction, ultimately triggering various diseases [6].
Mitochondrial protein homeostasis
Proteolysis is also one of the mechanisms of mitochondrial quality control, responding to damage caused by oxidative stress, misfolded proteins, damaged proteins, or defects in the electron transport chain. When discussing mitochondrial proteolysis, the most important aspect is mitochondrial proteases.
Mitochondrial proteases can degrade defective proteins in different mitochondrial compartments. In the matrix, multiple enzymes work together to degrade misfolded, damaged, and oxidized proteins, as well as to turnover some metabolic enzymes, forming the CLPXP complex and Lon protease homolog (LONP). Proteolysis generates peptides, which can be exported to the cytosol or further degraded into amino acids by presequence peptidase (PITRM1). In the intermembrane space, HTRA2 degrades misfolded, damaged, and oxidized proteins.
Statistics show that about two-thirds of the 1,200 mitochondrial proteins are located in the matrix, where the major matrix AAA proteases (such as LONP and CLPP) play an important role in the protein folding homeostasis control mechanism of mitochondria. Mutations in these proteases are associated with human genetic diseases. For example, mutations in the human LONP1 gene can lead to CODAS syndrome. Mutations in the human CLPP gene can cause Perrault syndrome, among others. In summary, mitochondrial proteolysis is considered crucial for maintaining mitochondrial function.
Mitochondrial autophagy degradation
Mitophagy primarily achieves quality control by removing damaged mitochondria. One of the most well-defined mechanisms of mitophagy is the PINK1/Parkin pathway; however, damaged mitochondria can also be eliminated through other autophagic pathways, including BCL2 interacting protein 3-like (BNIP3L) or FUN14 domain-containing 1 (FUNDC1) dependent mitophagy, as well as ULK1 and ATG5 independent non-classical autophagy. Additionally, mitochondria can be cleared by Pink1-Park2 dependent mitochondrial-derived vesicles. Mitochondria may be isolated within vacuoles and subsequently expelled from dying cells. They may also be secreted through a mitophagy-mediated mechanism involving mitosis [8].
Ub dependent pathway and Ub independent pathway of mitochondrial autophagy
As research progresses, an increasing number of human diseases have been linked to widespread mitochondrial defects. When mitochondria are under excessive stress or when their quality control processes fail, cells, tissues, and even entire organisms respond, and mitochondrial dysfunction can lead to the onset of metabolic, immune inflammatory, and neurological diseases [11-12].
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