Mitochondria participate in energy and free radicals production, cell metabolism, cell death, and inflammation in the brain (Martin, 2010; Yin et al., 2016; Stefanatos and Sanz, 2018; Bader and Winklhofer, 2020). Mitochondria are the primary sites of ATP production as well as catabolic biochemical processes such as glycolysis, tricarboxylic acid (TCA) cycle, and oxidative phosphorylation (OXPHOS). At synapses, neurons in the brain exchange chemical and electrical signals with one another. Maintaining electrochemical gradients, liberating and recycling synaptic vesicles, and other very energy-intensive procedures rely on mitochondrial ATP synthesis (Devine and Kittler, 2018). It has been predicted that axonal terminals consume 4.5 × 10⁸ ATP during an action potential (and downstream synaptic events), compared to 3 × 10⁶ ATP used by resting potentials and housekeeping (Harris et al., 2012). The ATP-dependent membrane pumps, such as Na⁺/K⁺ ATPase and Ca²⁺ ATPase, are powered by about 55% of the total ATP produced by neurons in order to maintain the resting potential by resetting ionic gradients (Harris and Attwell, 2012). In addition, synaptic vesicle recycling also consumes a significant amount of energy. Each glutamate synaptic vesicle recycling event requires more than 2 × 10⁴ ATP molecules, and in order to restore ionic gradients at a steady state, 1 × 10⁶ ATP molecules must be restored within each individual neuron terminal (Rangaraju et al., 2014). Besides that, the process of cargo transportation along axons, which is carried out by motors, kinesins, and cytoplasmic dynein, is also ATP-dependent (Gibbs et al., 2015). Therefore, mitochondrial ATP synthesis is essential to keep the brain functioning normally.

Glucose serves as the main source of energy in neurons. Initially, glucose catabolism generates pyruvate, which is then transferred to mitochondria for TCA and OXPHOS (Mergenthaler et al., 2013). By combining electron transport with the phosphorylation of ADP on the inner mitochondrial membrane (IMM), OXPHOS produces ATP. NADH CoQ reductase (complex I), succinate dehydrogenase (complex II), ubiquinol-cytochrome c reductase (complex III), cytochrome c oxidase (complex IV), and ATP synthase (complex V) are all involved in the process (Sousa et al., 2018; Vercellino and Sazanov, 2022).

Free radicals, particularly ROS, are generated by mitochondria. ROS acts a significant role in the regulation of multiple neuronal cell life processes, including nucleic acid oxidation, immune response, and NF-κB pathway. The major source of free radicals, also known as “mitochondrial ROS,” is the electron transport chain (ETC). There is a strong correlation between the rate of ROS production, mitochondrial membrane potential (MMP), and the activity of the ETC complexes (Islam, 2017; Kalpage et al., 2019).

To maintain organ size and function, mitochondria are required for cell death processes such as apoptosis, necroptosis, pyroptosis, and ferroptosis (Bock and Tait, 2020). The most widely understood mitochondria-related mechanism among them is apoptosis. Mitochondrial apoptosis also referred to as intrinsic apoptosis, is dependent on mitochondrial outer membrane permeabilization (MOMP). The procedure enables the release of proteins from the mitochondrial intermembrane space into the cytoplasm, which causes cell death. The establishment of functional circuitry, upkeep of healthy cell bodies and axons, promotion of myelination, and effective synaptic contact with target muscle are all facilitated by mitochondrial apoptosis in the brain (Buss et al., 2006; Fricker et al., 2018).

Under certain stress conditions, the outer and inner membrane of mitochondria are damaged, and mitochondrial components such as mitochondrial DNA (mtDNA), formyl peptides, cytochrome c (cyto c) and cardiolipin are released into the cytoplasm, which is regarded as danger-associated molecular patterns (DAMPs), inducing the assembly and activation of the inflammasome, the release of cytokines and the elicitation of innate immune responses (Bader and Winklhofer, 2020). DAMPs released by mitochondria activate microglia in the brain, which represent the primary form of immune defense. In addition to oxidative stress, metabolism, and OXPHOS regulation, mitochondria play an important role in neuroinflammation (Regen et al., 2017; Gu et al., 2021; Zhao et al., 2021).

Mitochondria, as highly dynamic organelles, participate in calcium networks and apoptosis, which are coupled to molecular patterns signaling, amino acid and lipid metabolism, and cell death. Thus, the maintenance of mitochondrial integrity and homeostasis is critical, which is accomplished through continuous fusion and fission. The process by which two mitochondria fuse into one is known as mitochondrial fusion. Because of the double membranes, mitochondrial fusion includes both outer and inner membrane fusion. Three large dynamin-related GTP-hydrolyzing enzymes, mitofusin 1 (MFN1), mitofusin 2 (MFN2), and optic atrophy 1 (OPA1) are involved in the fusion process (Bertholet et al., 2016; Chan, 2020). In particular, MFN1 and MFN2 are localized on the outer mitochondrial membrane (OMM) and are required for outer membrane fusion (Santel and Fuller, 2001; Rojo et al., 2002; Koshiba et al., 2004). Trans interactions between mitofusin are commonly accepted to mediate the tethering of mitochondria during the fusion process because they are present on opposing mitochondrial membranes and form homo-oligomeric and heterooligomeric complexes for fusion. Models of outer membrane fusion have been proposed. The crystal structures of the MFN1 suggest that an intermolecular interface of the globular GTPase domains modulates membrane tethering (Cao et al., 2017; Yan et al., 2018), whereas another model indicates that the C-terminal domain is also needed (Koshiba et al., 2004; Franco et al., 2016). It has recently been suggested that mitochondrial fusion tethers outer membranes through nucleotide-dependent dimerization (Qi et al., 2016; Cao et al., 2017). Following outer membrane fusion, OPA1 mediates mitochondrial inner membrane fusion. OPA1 is found in two topologically distinct isoforms in different tissues due to alternative splicing and proteolytic processing by mitochondrial proteases OMA1 and YME1L (Xiao et al., 2014; Wai et al., 2015; Anderson et al., 2020). Long-form OPA1 (L-OPA1) and cardiolipin are sufficient to facilitate membrane fusion, and loss of OMA1 delays neurodegeneration by preventing stress-induced OPA1 cleavage processing in mitochondria (Korwitz et al., 2016; Ban et al., 2017). In the OPA1-null cells, mitochondria could only show mitochondrial outer membrane fusion but never progress to inner membrane fusion. In this case, mitochondria appear to fission (Song et al., 2009; Mishra et al., 2014).

Fission is undeniably important for mitochondrial division and quality control, and dynamic-related protein 1 (Drp1) plays a key role in this process. Three Drp1 receptors, mitochondrial fission factor (MFF), mitochondrial dynamics proteins 49 (MiD49), and mitochondrial dynamics proteins 51 (MiD51), are all involved in recruiting Drp1 from the cytoplasm to the OMM. A fission defect similar to Drp1 depletion is generated by the loss of any of the receptors, which causes the mitochondria to elongate noticeably (Losón et al., 2013; Osellame et al., 2016; Otera et al., 2016). Fission 1 (Fis1), another OMM-located protein, has also been shown to recruit Drp1. Overexpression of Fis1 in cells promotes mitochondrial fragmentation, however, deletion of the FIS1 gene has no effect on mitochondrial morphology or Drp1 recruitment to mitochondria (Yoon et al., 2003; Stojanovski et al., 2004; Otera et al., 2010). Drp1 undergoes structural changes after being recruited to mitochondria, constricting the mitochondrial tubule and inducing mitochondrial fission. The cryo-EM studies indicate that cardiolipin, a lipid enriched in mitochondrial membranes, can modulate the Drp1 structure and thus activate the fission process (Figure 2A; Francy et al., 2017).

Autophagy is an important quality control system in the nervous system. In mammals, three different types of autophagy processes have been described: macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). The primary mechanism of MQC in cells is the macroautophagic degradation of mitochondria, or mitophagy, which is necessary for basal mitochondrial turnover.

In the process of mitophagy, dysfunctional mitochondria are first detected, then separated from the mitochondrial network, and recruited by the mitophagosome. The mitophagosome structures are formed in the absence of the ATG8 family proteins, which are classified as microtubule-associated protein light chain 3 (LC3, including LC3A, LC3B, and LC3C) and GABARAP (GABARAP, GABARAP-L1, and GABARAP-L2) subfamilies. Fusion of mitophagosome with lysosomes for degradation is necessary for the last stage of the elimination of damaged mitochondria (Tsuboyama et al., 2016; Onishi et al., 2021). Four major mitophagy pathways include serine/threonine-protein kinase PINK1 (PINK1)/E3 ubiquitin-protein ligase parkin (Parkin)-mediated mitophagy, Bcl-2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3)/NIP3-like protein X (NIX)-regulated mitophagy, FUN14 domain containing 1 (FUNDC1)-mediated mitophagy, and lipid-related pathways (Figure 2B). To trigger the degradation process, members of the ATG8 family should interact with all four pathways.

PINK1/Parkin-mediated mitophagy is the most well-known pathway. PINK1 is found on the IMM of normal mitochondria and is rapidly degraded by the mitochondrial membrane peptidase and presenilin-associated rhomboid-like protease (PARL) (Mokranjac and Neupert, 2007; Meissner et al., 2011). As a result, PINK1 remains at a low level under healthy conditions. However, when the inner membrane potential is depolarized, PINK1 moves to the OMM instead of IMM to form a dimer and is auto-phosphorylated at Ser228 and Ser402 residues (Okatsu et al., 2012). After being phosphorylated at Ser65 in its ubiquitin-like (Ubl) domain and activated by PINK1, Parkin, one of the E3 ubiquitin ligases, ubiquitinates its substrates like mitofusin (Kondapalli et al., 2012; Shiba-Fukushima et al., 2012; Koyano et al., 2014; Onishi et al., 2021). The autophagy adaptors, such as OPTN and NDP52, are phosphorylated by TANK-binding kinase 1 (TBK1), which recognizes these poly-ubiquitin chains, and binds with autophagy-related ATG8 family proteins via LIR motif, leading to mitophagy (Narendra et al., 2010; Kane et al., 2014; Kazlauskaite et al., 2014; Heo et al., 2015; Okatsu et al., 2015; Ordureau et al., 2015).

Unlike PINK1/Parkin, the BNIP3/NIX pathway is activated independently of changes in mitochondrial membrane potential (Rikka et al., 2011). In the normal state, BNIP3 is typically expressed as an inactive monomer in the cytoplasm, but under the hypoxia condition, BNIP3 is up-regulated, homodimerized, and anchored to the OMM by its C-terminal domain, while simultaneously exposing its N-terminal domain to the cytoplasm (Ray et al., 2000; Kubli et al., 2008; Hanna et al., 2012). At the N-terminal domain of BNIP3, the LC3-interacting region (LIR) motif recognizes and binds LC3, and mutations in the LIR motif prevent the contact with LC3, resulting in mitophagy abnormalities. Besides, phosphorylation at Ser17 and Ser24 near the LIR motif of BLIP3 is also important for BNIP3-LC3 interactions (Zhu et al., 2013). NIX is homology to BNIP3 and contains an LIR motif binding to ATG8 family members LC3A, LC3B, GABARAP, GABARAP-L1, and GABARAP-L2 among others (Hamacher-Brady et al., 2007; Sandoval et al., 2008; Novak et al., 2010). Ser34 and Ser35 of NIX, two serine residues close to the LIR motif, are phosphorylated similarly to BNIP3 in order to stabilize NIX-LC3 interactions and induce mitophagy (Rogov et al., 2017).

Additionally, the FUN14 domain containing 1 (FUNDC1) is also an OMM protein that has an LIR motif. It contains a characteristic LIR motif close to the N-terminus and three transmembrane domains (Liu et al., 2012). Phosphorylation and dephosphorylation on residues Ser13 and Tyr18 near the LIR motif of FUNDC1 regulate the process of mitophagy. Under hypoxia conditions, FUNDC1 interacts with LC3 via phosphoglycerate mutase family member 5 phosphatase (PGAM5) dephosphorylation at Ser13, and FUNDC1 phosphorylated by CK2 can reverse the effect of PGAM5 on mitophagy activation (Chen G. et al., 2014). In addition, SRC tyrosine kinase mediates the phosphorylation of Tyr18 to negatively regulate the FUNDC1-LC3 interactions field (Chen et al., 2016). Moreover, the phosphorylation of Ser17 in FUNDC1 by ULK1 enhanced the interaction between FUNDC1 and LC3, which could promote the mitophagy process (Wu et al., 2014).

Likewise, lipids including cardiolipin, cholesterol, and fatty acids have a role in the regulation of mitophagy. Among them, cardiolipin is a mitochondria-specific phospholipid located in IMM and is involved in receptor-mediated mitophagy in cells (Chu et al., 2013). When oxidized, cardiolipin is redistributed and translocated from IMM to OMM in damaged mitochondria and recognized by LC3. This process is coordinated by a hexameric intermembrane space protein, NDPK-D. The knockdown of endogenous NDPK-D decreases cardiolipin externalization and mitochondrial degradation (Kagan et al., 2016). Meanwhile, fatty acids could support the stability of PINK1 and translocation of the Parkin protein, participating in the regulation of mitophagy in the presence of PINK1. In the meantime, it has been shown that cholesterol has a dual role in PINK1/Parkin-mediated mitophagy (Roca-Agujetas et al., 2021).

Micromitophagy, which is defined as mitochondrial degradation independent of mitophagosomes, is another MQC mechanism that ensures mitochondrial homeostasis (Figure 2C; Wang et al., 2022). Under oxidative stress, mitochondria can generate mitochondrial-derived vesicles (MDVs) to proceed micromitophagy. In mammalian cells, MDVs formation is required OMM protein TOM20, or PINK1, Parkin, and soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs). Recognition and initiation of micromitophagy are different from the mechanism mediated by canonical autophagy regulators such as ATG5 or LC3 (Soubannier et al., 2012; McLelland et al., 2014, 2016; König et al., 2021). Internalization of MDVs into the lysosomal lumen for degradation occurs following the formation of MDVs (Soubannier et al., 2012; Wang et al., 2022). An alternative micromitophagy mechanism known as spermatogenesis-associated protein 18 (SPATA18; also called Mieap)-induced accumulation of lysosome-like organelles within mitochondria (MALM) is characterized by the transfer of lysosomal proteins into mitochondria to destroy the oxidized mitochondrial protein. This process varies from MDVs uptaking microautophagic payloads into lysosomes (Kitamura et al., 2011; Nakamura et al., 2012). Under mitochondrial stress, Mieap is up-regulated and works with BNIP3 to promote MALM (Nakamura et al., 2012). When mitochondria are severely damaged or MALM is inhibited, Mieap-induced vacuoles (MIVs) uptake the entire damaged mitochondria into the lysosome for decay (Kitamura et al., 2011; Miyamoto et al., 2011). Although the micromitophagy processes have been characterized in yeast and some mammalian cells such as hepatocytes, its role in brain and brain-related diseases need to be further investigated (Kissová et al., 2007; Bhatia-Kiššová and Camougrand, 2010; Lemasters and Zhong, 2018).

Mitochondrial proteome is encoded by both nuclear- and mitochondrial-genome. The fidelity and synchronization of these two protein synthesis systems are essential for ATP production and mitochondrial function. The nuclear-encoded proteins are synthesized by cytosolic ribosomes and imported into mitochondria by elaborate machinery embedded in the outer and inner mitochondrial membrane. During this coordination, the production of mitochondrial encoded proteins is regulated by the levels of imported proteins, preventing the redundant unassembled subunits (Ott et al., 2016; Priesnitz and Becker, 2018). The mitochondrial proteases could remove the unassembled proteins of the IMM. Furthermore, upon being imported into mitochondria, proteins synthesized by cytosolic ribosomes are monitored by mitochondrial proteases. Mitochondria have various mitoproteases, which can be divided into processing peptidases, ATP-dependent peptidases, and other mitochondrial peptidases (Deshwal et al., 2020). Among them, mitochondrial processing peptidases remove sorting signals from newly imported nuclear-encoded proteins, which is required for the maturation of many mitochondrial proteins (Mossmann et al., 2012; Poveda-Huertes et al., 2017; Deshwal et al., 2020). The mitochondrial processing protease MPP, for example, cleaves off mitochondrial targeting sequences (MTSs) in the matrix (Mach et al., 2013). Meanwhile, the inner membrane protease (IMMP) or ATP23 promotes the maturation of some proteins into the intermembrane space (IMS) (Weckbecker et al., 2012).

Another type of MQC-related protease is ATP-dependent proteases, which are the core consistency of the mitochondrial proteolytic system, activating in all mitochondrial compartments. The LONP1, caseinolytic mitochondrial matrix peptidase (CLPXP), m-AAA protease, and i-AAA protease are the four ATP-dependent proteases. LONP1 regulates mitochondrial oxidative phosphorylation (OXPHOS) via degrading damaged aconitase, and enzyme of the Krebs cycle in the mitochondrial matrix (Figure 2D; Bota and Davies, 2016). Besides, LONP1 modulates mitochondrial gene expression and some protein maturation (Lagouge et al., 2015; Zurita Rendón and Shoubridge, 2018). LONP1 also facilitates degrade COX4-1 to promote the assembly of the terminal electron transport chain (ETC) enzyme cytochrome c oxidase (Sepuri et al., 2017). Because of the critical role of LONP1 in mitochondrial functions, abnormal LONP1 causes a variety of diseases in humans. CLPXP, other than LONP1, is also reported to participate in the degradation of damaged OXPHOS complex I and II subunits (Seo et al., 2016). Meanwhile, CLPXP regulates gene expression by controlling the mitochondrial RNA (mtRNA) stability (Matsushima et al., 2017).

The m-AAA and i-AAA proteases are mitochondrial membrane-localized proteases (Figure 2D). They are necessary for the proteolysis of misfolded or damaged proteins and some IMM proteins, which helps to maintain the stability of mitochondria. In mammalian mitochondria, the m-AAA protease is composed of either an AFG3L2 homohexamer or an AFG3L2 and SPG7 heterohexamer. The hexameric AAA protease p97 (VCP) has a critical role in the degradation of outer mitochondrial membrane proteins, such as MFN1 (Xu et al., 2011), and the i-AAA protease YME1L removes translocase of the inner membrane 17A protein (TIM17A) to reduce protein import into mitochondria under stress and also regulates mitochondrial lipid composition by degradation of some lipid transfer proteins that shuttle phospholipids across the intermembrane space between the OMM and the IMM (Rainbolt et al., 2013; Saita et al., 2018). Additionally, the IMM proteases also regulate mitochondrial morphology by cleaving OPA1. Deletion of YME1L in the nervous system causes spinal cord axon degeneration in mice. Ablation of metalloproteinase OMA1, which is located on IMM, prevents neurodegeneration in YME1L-mutant mice, demonstrating the role of proteolytic processing in regulating mitochondrial function and physiology in the brain (Sprenger et al., 2019). In addition, the OMM-located ATPase family AAA domain-containing 1 (ATAD1) may promote the extraction and degradation of mislocalized tail-anchored (TA) proteins to preserve mitochondrial integrity, performing a crucial role in the regulation of synaptic activities in neurons (Chen Y. C. et al., 2014; Han et al., 2020).

Neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), are characterized by the loss of selective neuron subtypes in the CNS. It has been demonstrated that the aberrant MQC plays a significant role in the progression of these diseases. If we take AD as an example, the mitochondrial fission and fusion proteins are disrupted in the hippocampus in various AD animal models and AD patients. The fission protein Fis1 is up-regulated, while fusion proteins MFN1, MFN2, and OPA1 are down-regulated (Wang et al., 2009). Moreover, Drp1 phosphorylation at Ser616 is higher in the brains of AD patients (Wang et al., 2009). Even though Parkin-mediated mitophagy was initially characterized in PD, the Parkin protein level has been shown higher and Parkin-mediated mitophagy is ineffective in the brains of AD patients (Ye et al., 2015). In addition, abnormal MQC and dysfunctional mitochondria are associated with chronic inflammation. It is well-known that, activated microglia function as innate immune cells in the CNS. In AD mice and patients, as observed, microglia stimulate phagocytosis, clearance, and degradation to minimize the accumulation of Aβ (Graeber et al., 2011). However, chronic microglia activation leads to the secretion of inflammatory cytokines and further neuronal dysfunction (Jiang et al., 2012). These findings suggest that aberrant MQC contributes to the development of neurodegenerative diseases.

Ischemic stroke is one of the major diseases that cause death and disability of the nervous system. Although revascularization via reperfusion has led to a reduction in the mortality rate of ischemic stroke, the reperfusion itself also causes additional damage to the brain tissue, which is called ischemia-reperfusion (I/R) injury. It has been suggested that several MQC-related processes contribute to I/R damage. The removal of damaged mitochondria and mitochondrial apoptosis of neuron cells is aided by mitochondrial fission and mitophagy during cerebral I/R injury (Kumar et al., 2016; Zhao et al., 2018b). Overexpression of Sirtuin 3 (Sirt3) can inhibit mitochondrial fission and trigger pro-survival signals in neurons subjected to I/R injury (Zhao et al., 2018a). Furthermore, excessive mitochondrial fission stimulates energy imbalance and mtDNA damage, which worsens brain damage (Yue et al., 2015).

Epilepsy is typified by recurrent unprovoked seizures of neurons. Mitochondrial stress and MQC are involved in the pathogenesis of epilepsy. The levels of MQC-related proteins OPA1, MFN2, MFF, and Drp1 are elevated in the mice models of acute maximal electroshock and 6 Hz 44 mA seizure (Cho et al., 2022). MQC-related serine peptidase LONP1 is up-regulated in the mitochondria during status epilepticus (SE), and LONP1 knockdown enhances SE-induced mitochondrial apoptosis in neuron (Kim et al., 2021).

Mitochondrial quality control-related gene mutation or abnormal expression is related to brain dysplasia (Table 1). In cultured neurons, over-expression of MFN2 mutation disrupted axonal mitochondrial positioning and promoted axon degeneration (Detmer and Chan, 2007; Misko et al., 2012). Moreover, neuron-specific knockout mice show that MFN2 is required for dendritic outgrowth, axonal projection, and survival (Chen et al., 2003, 2007; Lee et al., 2012; Pham et al., 2012). It has been improved that OPA1 can protect neurons from excitotoxicity (Jahani-Asl et al., 2011; Nguyen et al., 2011; Kushnareva et al., 2013). Some research shows heterozygous OPA1 mutations both on the GTPase or GED domains lead to a decrease of protein quantity and mice of Opa1 heterozygous mutations have become autosomal dominant optic atrophy (DOA) models. These DOA mice perform retinal ganglionic cell (RGC) loss or dysfunction and optic nerve dysfunction including axonal degeneration and demyelination (Williams et al., 2011). Moreover, mutations of mitophagy-associated gene PARK6 (encoded PINK1) or PARK2 (encoded Parkin) contribute to autosomal recessive juvenile parkinsonism (Lücking et al., 1998; Valente et al., 2001, 2002, 2004).