The interconnective role of the UPS and autophagy in the quality control of cancer mitochondria

Abstract

Uncontrollable cancer cell growth is characterized by the maintenance of cellular homeostasis through the continuous accumulation of misfolded proteins and damaged organelles. This review delineates the roles of two complementary and synergistic degradation systems, the ubiquitin-proteasome system (UPS) and the autophagy-lysosome system, in the degradation of misfolded proteins and damaged organelles for intracellular recycling. We emphasize the interconnected decision-making processes of degradation systems in maintaining cellular homeostasis, such as the biophysical state of substrates, receptor oligomerization potentials (e.g., p62), and compartmentalization capacities (e.g., membrane structures). Mitochondria, the cellular hubs for respiration and metabolism, are implicated in tumorigenesis. In the subsequent sections, we thoroughly examine the mechanisms of mitochondrial quality control (MQC) in preserving mitochondrial homeostasis in human cells. Notably, we explored the relationships between mitochondrial dynamics (fusion and fission) and various MQC processes-including the UPS, mitochondrial proteases, and mitophagy-in the context of mitochondrial repair and degradation pathways. Finally, we assessed the potential of targeting MQC (including UPS, mitochondrial molecular chaperones, mitochondrial proteases, mitochondrial dynamics, mitophagy and mitochondrial biogenesis) as cancer therapeutic strategies. Understanding the mechanisms underlying mitochondrial homeostasis may offer novel insights for future cancer therapies.

Keywords: Autophagy-lysosome; Cancer therapy; Mitochondrial chaperones; Mitochondrial proteases; Mitophagy; Protein quality control; UPS.

Fig. 1

Protein and organellar quality control mechanisms of mitochondria. a The UPS: E3 ubiquitin ligases, such as MARCH5, facilitate the ubiquitination of mitochondrial OMM proteins, thereby tagging them for proteasomal degradation. b Mitochondrial chaperones and proteases: These proteins play a crucial role in maintaining the quality and functionality of mitochondrial proteins. c Mitochondrial morphology: This is dynamically regulated through the processes of fission and fusion. d Mitophagy: This process selectively eliminates dysfunctional, excess, or aged mitochondria to maintain cellular health. e Mitochondrial biogenesis: This process regulates the number and functionality of mitochondria to fulfill the energy and metabolic requirements of the cell

Fig. 2

Orchestration of protein homeostasis in inner mitochondrial compartments by mitochondrial chaperones and mitoproteases. Precursor proteins, synthesized in the cytosol, enter mitochondria via the translocase of the outer membrane (TOM) complex and the presequence translocase (TIM23) complex. The membrane potential (Δψm) drives protein translocation through TIM23 into the matrix and inner membrane. Mitochondrial HSP70 (mtHSP70), part of the presequence translocase-associated motor (PAM), completes ATP-dependent import into the matrix. The mitochondrial processing peptidase (MPP) removes the presequence, followed by protein folding mediated by chaperones mtHSP70 and HSP60-HSP10. Misfolded proteins resulting from impaired chaperone function are degraded by matrix proteases CLPXP and LON. The inner mitochondrial membrane (IMM) houses two AAA proteases: the i-AAA protease degrades proteins in the intermembrane space (IMS) and outer mitochondrial membrane (OMM), while the m-AAA protease targets inner membrane and matrix proteins. This quality control system, encompassing import, folding, and degradation mechanisms, is crucial for maintaining mitochondrial function and cellular health

Fig. 3

The damaged mitochondria turnover. a Mitochondrial dynamics: fusion and fission dilute damaged parts and remove dysfunctional mitochondria. b Mitophagy: a dedicated mechanism to eliminate damaged mitochondria. c Mitocytosis: a novel quality control pathway in migrating cells where damaged mitochondria are encapsulated into “migrasomes” budding from elastic fibers and exported from the cell. d Mitochondrial-derived vesicles (MDVs): oxidative stress stimulates special vesicles to remove damaged materials from stressed mitochondria. e Mitochondrial biogenesis: generating new mitochondria to replace lost ones

Fig. 4

Crosstalk between UPS and mitophagy promotes mitochondria homeostasis. Left: The UPS and mitoproteases coordinated with mitochondrial fusion promotes the efficient and rapid resolution of mild mitochondrial damage. As the mitochondrial membrane potential gradually decreases, the emphasis on quality control mechanisms shifts towards fission and mitophagy. Right top: The UPS primarily degrades soluble OMM proteins and regulates proteins involved in mitochondrial dynamics such as MFN1/2, thereby modulating mitochondrial fusion and fission. Under normal conditions, PARL stimulates retro-translocation and degradation of the PINK1 kinase, which is associated with mitophagy. On import into mitochondria, OPA1 can be cleaved by the YME1L and metalloproteinase OMA1, which results in the formation of short and long OPA1 forms. Right middle: The higher membrane potential (higher △Ψm) tends to fuse, mediated by MFN1/2 and L-OPA1. In contrast, mitochondria with a lower membrane potential (lower △Ψm) tend to undergo fission and mitophagy. DRP1, binding to receptors on OMM, executes fission. S-OPA1 generated by OMA1 further promotes this process. Moreover, Parkin plays a dual role—regulating mitochondrial dynamics proteins as E3 ligases while mediating mitophagy. Right below: The PINK1/Parkin-dependent mitophagy is the main surveillance mechanism for damaged mitochondria, and PINK1 recruits Parkin to ubiquitinate OMM proteins in response to impaired membrane potential. These proteins are recognized by selective autophagy receptors like OPTN and NDP52, which damage mitochondria to autophagosomes. In PINK1/Parkin-independent mitophagy, BNIP3L/FUNDC1/PHB2/CL can directly interact with LC3 to induce the removal of dysfunctional mitochondria

Fig. 5

Mitochondrial quality control (MQC) research over the past decade. Over the past decade, MQC research has made significant progress, with many important discoveries that have significantly advanced our understanding of this critical cellular process. However, owing to space constraints, this review could not cover all the key milestones [–, , , , , –218]

Fig. 6

The major role of MQC in tumors. a Mitochondrial protein maintenance acceleration: The UPS is overactivated, and mitochondrial chaperones and proteases are upregulated in tumors, facilitating rapid clearance of misfolded proteins. b Mitochondrial dynamics imbalance: excessive mitochondrial fission supports tumor progression by enhancing energy supply, promoting metabolic reprogramming, increasing anti-apoptotic capacity, fostering drug resistance, and facilitating metastasis. c Overactivated mitophagy: this process helps tumor cells maintain metabolic homeostasis and adapt to stressful environments by selectively removing damaged or unnecessary mitochondria, thereby promoting survival under adverse conditions. d Accelerated mitochondrial biogenesis: Tumor cells exhibit highly active mitochondrial biogenesis, resulting in increased mitochondrial density. This adaptation provides both energy and metabolic intermediates crucial for tumor proliferation and survival