Mitochondrial diseases form a diverse group of heritable disorders caused by a wide spectrum of mutations in nuclear or mitochondrial genes (1, 2). The nuclear DNA encodes over 1,000 mitochondrially localizing proteins, translated in the cytoplasm, and translocated to the mitochondria. The mitochondrial (mt-)DNA encodes 37 genes including 22 tRNAs and two rRNAs. The mt-DNA is essential for mt-DNA-specific translation of the 13 encoded respiratory chain subunits (3). Dysfunction in mitochondrial respiratory chain function and cellular energy production affects different tissues, owing to critical dependence of the heart on oxidative metabolism; cardiac involvement in mitochondrial disease is common and may occur as the principal clinical manifestation or part of multisystem disease (4, 5). Cardiovascular involvement in mitochondrial disease resulted in lower survival rates to age 16 years than in patients without heart disease (6).

C1QBP comprises 6 exons located on the short arm of chromosome 17p13.2. It is highly conserved through evolution (7): the human and rat/mouse cDNA sequences are almost identical (8, 9). C1QBP encodes the complement component 1Q subcomponent-binding protein (C1QBP, p32). This widely expressed multifunctional protein is predominantly localized in mitochondrial matrix (10, 11). Its N-terminal mitochondrial targeting peptide is proteolytically processed after it reaches the mitochondrial matrix. Here it forms a doughnut-shaped homotrimeric complex (12–14).

C1QBP is reported to exert pleiotropic effects on many cellular processes, including mitochondrial homeostasis, mitochondrial oxidative phosphorylation (OXPHOS) and in nucleus–mitochondrial interactions, inflammation, and cancer (15–19). Biallelic C1QBP mutations were recently identified manifesting as combined oxidative phosphorylation deficiency (COXPD) in an autosomal recessive inherited pattern. This involved multiple systems including heart, liver, skeletal muscle, eye and nervous system (20–24). However, cardiomyopathy, whose exact underlying mechanisms remain elusive, is the major phenotype. This review summarizes physiological functions of C1QBP, its mutation-associated mitochondrial cardiomyopathy, and current disease models.

C1QBP is highly expressed in cells with substantial energy metabolism such as cardiac and skeletal muscle (25). It can exist in numerous cellular compartments but is predominantly targeted to the mitochondria reflecting the mitochondrial targeting sequence in its 73N-terminal amino acids. The C1QBP crystal structure reveals three monomers forming a doughnut-shaped quaternary structure with an unusually asymmetric surface charge distribution. It shows a fold comprising seven consecutive antiparallel β-strands flanked by one N-terminal and two C-terminal α-helices (25–29).

Mitochondrial C1QBP is essential for OXPHOS. It pivotally supports translation of the mitochondrially encoded respiratory chain protein complexes I, III, IV and V (30). C1QBP knockdown decreased complexes I, III, IV, and V but not complex II levels, reducing complex I and IV enzymatic activity (16). Chen et al. reported that C1QBP binds to the core, dihydrolipoyl-lysine-residue acetyltransferase (DLAT), component of the matrix multienzyme pyruvate dehydrogenase (PDH) complex (31). PDH is important in energy homeostasis, linking glycolysis and the tricarboxylic acid (TCA) cycle. PDH catalyzes pyruvate conversion to acetyl-CoA used in the TCA cycle to generate ATP (32). C1QBP regulates OXPHOS through binding to DLAT, providing a novel molecular mechanism by which C1QBP regulates cellular respiration (27).

C1QBP is required for development and maintenance of normal cardiac function (15). Cardiomyocyte specific C1QBP deletion resulted in contractile dysfunction, cardiac dilatation and fibrosis. C1QBP deficiency decreases COX1 expression and oxygen consumption rates, increased oxidative stress, further leading to cardiomyocyte dysfunction. In cardiomyocytes, C1QBP acts as an RNA and protein chaperone modulating mitochondrial translation and function (15). In addition, 5' adenosine monophosphate-activated protein kinase A (AMPKA) was constitutively phosphorylated, and eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) and ribosomal S6 kinase (S6K) were less phosphorylated in C1QBP deficient myocytes, suggesting impaired rapamycin signaling. Metabolic analysis also demonstrated an impaired urea cycle in C1QBP deficient hearts (15).

Mitochondrial morphology is closely linked to energy metabolism. Reduced OXPHOS and enhanced glycolysis correlates with mitochondria fragmentation and mitochondrial matrix expansion (33). C1QBP is required to maintain normal mitochondrial structure and is critical in protecting mitochondria from fragmentation and swelling by inhibiting OMA1-dependent proteolytic processing of the optic atrophy type 1 GTPase protein (OPA1) (15, 28). Cardiac mitochondria from C1QBP-deficient mice showed disordered alignment, enlargement and abnormalities in their internal structure (15). Furthermore, the mitochondrial network was fragmented rather than fibrillar when C1QBP was not expressed (16).

The crystal structure of C1QBP has been determined. This is compatible with an association with regulation of mitochondrial Ca²⁺. It can form a pore-like homotrimer that could serve as a high-capacity divalent cation storage protein. C1QBP contains 282 amino acid residues. Twenty three percent of these residues are glutamic and aspartic acids distributed on the trimer surface. This characteristic acidic surface is reminiscent of the major sarcoplasmic reticular Ca²⁺ storage protein calsequestrin (34). The latter modulates intracellular Ca²⁺ concentration and affects membrane Ca²⁺ transport rates into sarcoplasmic reticular vesicles. C1QBP may similarly modulate Ca²⁺ levels in the mitochondrial matrix (14). Xiao et al. proposed that C1QBP protein is additionally a positive regulator of mitochondrial Ca²⁺ uptake (35). Koo et al. and Choi et al. similarly confirmed that mitochondrial C1QBP protein has a regulatory effect on mitochondrial Ca²⁺ uptake (36–38). Oxidative metabolism strongly varies with mitochondrial Ca²⁺ levels (39). PDH, NAD-isocitrate dehydrogenase and oxoglutarate dehydrogenase are all regulated by intramitochondrial Ca²⁺ levels either directly or indirectly (40). C1QBP may thereby regulate mitochondrial OXPHOS by modulating Ca²⁺ concentrations (14).

C1QBP expression increases in multiple cancer cells in human, including breast, endometrial, ovarian, prostate, melanoma, lung, and colon cancer (41–49). C1QBP may be pivotal in tumor cell survival, growth and metastatic invasion through interacting with critical molecules, including those of the complement and kinin systems, in the tumor cell microenvironment (25). C1QBP may be needed to sustain tumor cell growth by maintaining respiration and OXPHOS. C1QBP knockdown tumor cell lines showed decreased complex I, III, IV, and V subunit levels (50). Zhang et al. (51) suggested that C1QBP further regulated protein kinase Cζ activity and modulated EGF-induced cancer cell chemotaxis. It was additionally identified as a novel regulator of cancer metastasis that may serve as a target for breast cancer therapy (50).

Finally C1QBP appears critical in inflammation processes and responses to infection (25). It binds to a wide variety of plasma and cell surface, and pathogenic microorganism proteins. It is critical in modulating fibrin formation, particularly at local sites of immune injury and/or inflammation and activating the kinin/kallikrein system. It is also able to generate the powerful vasoactive peptide bradykinin largely responsible for the swelling seen in angioedema (17–19).

Biallelic C1QBP mutations were first reported in four individuals by Feichtinger et al. (20). Biallelic C1QBP mutation caused a COXPD 33 (OMIM:617713). In the reported 12 cases with C1QBP mutations, phenotypes were typically severe, even fatal (20–24). They present at any age and cover a wide spectrum of clinical manifestations including intrauterine growth restriction, cardiorespiratory arrest, cardiac hypertrophy, cardiac failure, ventricular arrhythmias, hepatomegaly, exercise intolerance, progressive external ophthalmoplegia (PEO), cerebral hemorrhages/edema and nervous system dysfunction.

We summarize the structure and physiological functions of C1QBP and its mutation related clinical phenotypes. C1QBP localizes predominantly in the mitochondrial matrix and is essential for OXPHOS maintenance. Patients identified with C1QBP mutations showed combined respiratory-chain deficiencies and abnormalities in the heart, liver, kidney, skeletal muscle, eye and nervous system. Clinical manifestations included intrauterine growth restriction, cardiomyopathy, hepatomegaly, exercise intolerance, swallowing dysfunction, ptosis, PEO and peripheral nervous system dysfunction. The relationship between observed mitochondrial cardiomyopathy and the C1QBP mutations and its underlying mechanism requires further studies for its elucidation on the platforms of iPSC-CMs and animal models.

YZ wrote the original manuscript. YZ and CL-HH reviewed and edited the manuscript. All authors contributed to the article and approved the submitted version.

This work was supported by grants from National Natural Science Foundation of China (81974014 and 81470452); International cooperation project of Shaanxi Science and Technology Department (2019KW-072); Scientific research project of Xi'an Talent Program (XAYC200023) and Xi'an Children's Hospital Science Project (2020D01).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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