Mitochondrial quality control in human health and disease

Abstract

Mitochondria, the most crucial energy-generating organelles in eukaryotic cells, play a pivotal role in regulating energy metabolism. However, their significance extends beyond this, as they are also indispensable in vital life processes such as cell proliferation, differentiation, immune responses, and redox balance. In response to various physiological signals or external stimuli, a sophisticated mitochondrial quality control (MQC) mechanism has evolved, encompassing key processes like mitochondrial biogenesis, mitochondrial dynamics, and mitophagy, which have garnered increasing attention from researchers to unveil their specific molecular mechanisms. In this review, we present a comprehensive summary of the primary mechanisms and functions of key regulators involved in major components of MQC. Furthermore, the critical physiological functions regulated by MQC and its diverse roles in the progression of various systemic diseases have been described in detail. We also discuss agonists or antagonists targeting MQC, aiming to explore potential therapeutic and research prospects by enhancing MQC to stabilize mitochondrial function.

Keywords: Cancer; Cardiovascular disease; Digestive system disease; Kidney disease; Metabolic disease; Metabolism; Mitochondrial quality control; Nervous disease; Programmed cell death; Pulmonary disease.

Fig. 1

Molecular regulation of Mitochondrial quality control. a PGC-1α plays a central role in mitochondrial biogenesis. Several regulators, including AMPK, Sirts, and Ca²⁺, are involved in the regulation of PCG-1α expression and activity. In addition, PGC-1β is also involved in the mitochondrial biogenesis process. b Mitochondrial dynamics consists of fission and fusion. The fission-associated proteins (DRP1, FIS1, MFF, et al.) mediate the fission of mitochondria, a process receiving complex regulation by various factors such as endoplasmic reticulum and multiple kinases. The fusion event consists of mitochondrial outer membrane fusion mediated by MFNs and mitochondrial inner membrane fusion mediated by OPA1, similarly, they are subject to complex regulation at different stages of fusion. c The role of mitophagy is to remove damaged mitochondria promptly. There are two pathways of mitophagy, respectively, the PINK1/Parkin-dependent pathway and the PINK1/Parkin-independent pathway. Their common feature is the formation of autophagosomes that enclose damaged mitochondria and the complex regulation by multiple intracellular signals. Moreover, the presence of protein quality control systems in mitochondria removes misfolded mitochondrial proteins, and the accumulated unfolded proteins will promote mitophagy. AMPK AMP-activated protein kinaseBNIP3 BCL2 interacting protein 3, CaMK calcium/calmodulin-dependent protein kinase, DeAc deactylation, DRP1 dynamin-related protein 1, ETC electron transport chain, FAO fatty acid oxidation, FIS1 fission protein 1, FUNDC1 FUN14 domain containing 1, INF2 inverted formin 2, JNK Jun N-terminal kinase, LC3 microtubule associated protein 1 light chain 3, LONP1 lon protease 1, MAPK mitogen-activated protein kinases, MARCH5 membrane associated ring-CH-type finger 5, MDV mitochondria derived vesicle, Met MET proto-oncogene, MFF mitochondrial fission factor, MFN mitofusin, MiD mitochondrial dynamics, NDP52 nuclear dots protein 52, Nix NIP3-like protein X, Nrf2 nuclear factor E2-related factor 2, OMA1 OMA1 zinc metallopeptidase, OPA1 optic atrophy 1, OPTN optineurin, PGC-1α PPAR-γ coactivator-1α, PINK1 PTEN-induced kinase 1, Sirt1 sirtuin 1, TFAM mitochondrial transcription factor A, TFB1M mitochondrial transcription factors B1, TFB2M mitochondrial transcription factors B1, TNF-α tumor necrosis factor-α, Tom20 translocase of outer mitochondrial membrane 20, TORC transducer of regulated CREB (cAMP response element-binding protein), ULK1 unc-51 like autophagy activating kinase 1, UPS ubiquitin–proteasome system, VDAC voltage dependent anion channel, YME1L YME1 like 1 ATPase

Fig. 2

Physiological roles of mitochondrial quality control. a Mitochondria, as the core of energy metabolism, regulate their quality to adapt to the cellular environment under different bioenergy conditions. When nutrients are in excess, mitochondrial dynamics switch to division dominance and mitophagy is blocked. Under starvation conditions, the mitochondria fuse, and the mitochondrial autophagic flux is enhanced. Together, these regulations promote the balance of mitochondrial energy metabolism. b Mitochondria can act as calcium pools in cells, and there are extensive interactions between calcium ions and mitochondrial quality control to jointly regulate mitochondrial mass and calcium ion homeostasis. c Depolarizing mitochondria leads to oxidative stress. Mildly damaged mitochondria can fuse with healthy mitochondria to neutralize damage, and severely damaged mitochondria are cleared by mitophagy, but excessive mitophagy can also lead to oxidative stress. d Excessive mitochondrial fission is an early event in apoptosis, pyroptosis, and ferroptosis. Mitochondrial fragmentation promotes cytochrome and mtDNA release and causes oxidative stress. Furthermore, the regulation of ferroptosis correlates with mitophagy flux, and moderate mitophagy promotes the clearance of ROS, while excess mitophagy results in excess iron ions. e Mitochondria initiate fine kinetic processes to accommodate the mitochondrial genetic process in progeny during the cell cycle. Cyclin regulator CDK1 promotes protein import into the mitochondria to ensure mitochondrial energetic support during the cell cycle. Mitophagy reduces the pool of mitochondria in the cell, which would further limit the cell cycle. ATP adenosine triphosphate, BAX BCL2 associated X, CDK1 cyclin B/cyclin-dependent kinase 1, DRP1 dynamin-related protein 1, ETC electron transport chain, FIS1 fission protein 1, Fzo1 fuzzy onion 1, INF2 inverted formin 2, GTPase guanosine triphosphatase, MCU mitochondrial calcium uniporter, MFN mitofusin, Mgm1 mitochondria genome maintenance 1, mtDNA mitochondrial DNA, NCLX Na⁺/Ca²⁺/Li⁺ exchanger, NLRP3 NLR family pyrin domain containing 3, Nrf2 nuclear factor E2-related factor 2, OPA1 optic atrophy 1, PINK1 PTEN-induced kinase 1, RALBP1 ralA binding protein 1, ROS reactive oxygen species, STING stimulator of interferon response cGAMP interactor, TCA tricarboxylic acid, VDAC voltage-dependent anion channel

Fig. 3

Mitochondrial quality control and cancer. a The role of mitochondrial quality control varies in different tumors. Mitophagy could remove dysfunctional mitochondria and hinder the proliferation of tumor cells and, on the other hand, the clearance of apoptotic mitochondria can remove the oxidative stress adaptation of tumor cells and subsequently promote tumor cell apoptosis. Tumor cells tend to have highly active mitochondrial biogenesis, and the high density of mitochondria provides both energy and metabolic intermediates for tumor proliferation. b In tumor-associated macrophages, mitophagy promotes oxidative phosphorylation and the clearance of ROS, thereby promoting the M2 phenotype of tumor macrophages. c In T cells, the insufficiency of mitochondrial fission, mitochondrial biogenesis, and mitophagy leads to the depletion of effector T cells. d In NK cells, the hypoxic microenvironment promotes mitochondrial fragmentation, which leads to the failure of immune surveillance. ATP adenosine triphosphate, DRP1 dynamin-related protein 1, CCL2 C–C motif chemokine ligand 2, TAM tumor-associated macrophage, mTOC1 mammalian target of rapamycin complex 1, Akt v-akt murine thymoma viral oncogene homolog, PD-1 programmed cell death protein 1, NK natural killer, IL interleukin, mtDNA mitochondrial DNA, OXPHOS oxidative phosphorylation, PGC-1α PPAR-γ coactivator-1α, ROS reactive oxygen species, TME tumor microenvironment

Fig. 4

Mitochondrial quality control and cardiovascular disease. The common features of mitochondrial quality control in cardiovascular disease are the downregulation of mitochondrial biogenesis, a shift of mitochondrial dynamics to fission phenotypes, and the downregulation of mitophagy. In the early stage of most cardiovascular diseases, mitophagy is properly upregulated to compensate for mitochondrial quality disorders, but in the stage of disease progression, mitophagy is downregulated. Created by Biorender.com, accessed on 25 Aug 2023. DRP1 dynamin-related protein 1, MFN mitofusin, OPA optic atrophy, PGC-1α PPAR-γ coactivator-1α

Fig. 5

Mitochondrial quality control and nervous disease. a In amyotrophic lateral sclerosis, a downregulation of PGC-1α mediates a decrease in mitochondrial biogenesis, excessive mitochondrial fission, and impaired mitophagy, which are key features of the disease. b Ischemic brain injury exhibits similar mitochondrial phenotypic characteristics, and mitigating brain tissue damage and oxidative stress levels can be achieved through upregulation of mitochondrial biogenesis mediated by PGC-1α and mitophagy mediated by Parkin-2. c Accumulated Aβ in Alzheimer’s disease activates DRP1, leading to impaired mitochondrial dynamics. Additionally, Tau can interact with Parkin, affecting the clearance of damaged mitochondria. Dysfunctional mitophagy further accelerates Aβ accumulation, forming a positive feedback loop of mitochondrial damage. d Mutations in PRKN and PINK1 have been recognized as important genetic factors in Parkinson’s disease, and impaired mitophagy can further activate NLRP3, inducing neuroinflammation. e The key feature of Huntington's disease is the activation of DRP1 by mHtt, triggering severe mitophagy. Created by Biorender.com, accessed on 25 Aug 2023. DRP1 dynamin-related protein 1, mHtt mutant Huntingtin, PGC-1α PPAR-γ coactivator-1α, PINK1 PTEN-induced kinase 1, ROS reactive oxygen species

Fig. 6

Mitochondrial quality control and pulmonary disease. a In idiopathic pulmonary fibrosis, mitochondrial quality control dysfunction manifests as reduced mitochondrial biogenesis and downregulation of mitophagy. b Similarly, in chronic obstructive pulmonary disease, diminished mitochondrial biogenesis and impaired mitochondrial dynamics are observed. c Conversely, in bronchial asthma, mitochondrial biogenesis is upregulated, which is closely associated with the high demand for smooth muscle cell proliferation. d Notably, excessive mitochondrial fission is a key feature of acute lung injury, where increased mitochondrial biogenesis is beneficial. e Likewise, excessive mitochondrial fission is also a notable feature of pulmonary arterial hypertension. Created by Biorender.com, accessed on 25 Aug. 2023

Fig. 7

Mitochondrial quality control and digestive system diseases. Various digestive system diseases demonstrate a downregulation of mitochondrial biogenesis, excessive mitochondrial fission, and downregulation of mitophagy within the mitochondrial quality control system. a In hepatic ischemia–reperfusion injury, downregulation of sirt1 hinders the downstream mitochondrial biogenesis process, with alterations in Cox-2 and ALR expression levels also involved in the regulation of mitochondrial dynamics disruption. Additionally, ALR is implicated in the regulation of the PINK1 and Parkin-mediated mitochondrial translocation process, leading to impaired mitophagy. b In non-alcoholic fatty liver disease, upregulation of P2Y2R affects PGC-1α expression levels, consequently causing inadequate mitochondrial biogenesis. NR4A1 is involved in regulating excessive mitochondrial fission, while mitophagy defect is a notable feature of this disease. c In inflammatory bowel disease, insufficient mitochondrial biogenesis is controlled by SMYD5, and notably, excessive mitochondrial fission contributes to the activation of NLRP3 in intestinal inflammation. ALR augmenter of liver regeneration, BNIP3 BCL2 interacting protein 3, Cox-2 cyclooxygenase 2, DRP1 dynamin-related protein 1, FIS1 fission protein 1, MFN mitofusin, HO-1 heme oxygenase 1, I/R ischemia–reperfusion, NLRP3 NLR family pyrin domain containing 3, NR4A1 nuclear receptor subfamily 4 group A member 1, Nrf2 nuclear factor E2-related factor 2, OPA1 optic atrophy 1, PGC-1α PPAR-γ coactivator-1α, P2Y2R P2Y receptor 2, SMYD5 SET and MYND domain 5, Sirt1 sirtuin 1, SUMO small ubiquitin-like modifier