The role of FUNDC1 in mitophagy, mitochondrial dynamics and human diseases

Liu, Hui; Zang, Caixia; Yuan, Fang-Yu; Ju, Cheng; Shang, Meiyu; Ning, Jingwen; Yang, Yang; Ma, Jingwei; Li, Gen; Bao, Xiaoyong; Zhang, Dan

doi:10.1016/j.bcp.2021.114891

Cited by 43 publications

(34 citation statements)

References 103 publications

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“…Furthermore, it was revealed that not only was mitophagy inhibited, silencing FUNDC1 expression also reversed hypoxia-induced proliferation, migration and odontoblastic differentiation. FUNDC1-mediated mitophagy is associated with various cell activities ( 45 , 46 ). Wu et al ( 16 ) previously showed that upregulating the expression of FUNDC1 can stimulate human breast cancer cell proliferation and migration by increasing Ca 2+ influx.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia‑induced mitophagy regulates proliferation, migration and odontoblastic differentiation of human dental pulp cells through FUN14 domain‑containing 1

et al. 2022

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FUN14 domain-containing 1 (FUNDC1) is a receptor that has been previously reported to activate hypoxia-induced mitophagy. However, the potential role of FUNDC1 in the pathophysiology of dental pulp diseases remains unknown. Therefore, present study first collected tissue specimens from patients with pulpitis and from healthy individuals. The results of reverse transcription-quantitative PCR and immunohistochemical staining revealed markedly increased FUNDC1 and hypoxia-inducible factor-1α expression in pulpitis tissue specimens compared with those from healthy individuals. To provide a theoretical basis for the study of the occurrence, development and reparative mechanisms in the dental pulp after tissue injury, the present study then investigated the role of hypoxia-induced mitophagy in the regulation of proliferation, migration and odontoblastic differentiation in human dental pulp cells (HDPCs), in addition, to the possible involvement of FUNDC1. The surface markers and multipotent differentiation capabilities of HDPCs were performed by flow cytometry (surface markers), alizarin red (osteogenic capabilities), alcian blue (chondrogenic capabilities) and oil red O (adipogenic capabilities). Following culture under hypoxia conditions (1% O 2 ) for varying time periods, the proliferation, migration and odontoblastic differentiation of HDPCs were measured using Cell Counting Kit-8, wound healing and Transwell migration assays, alkaline phosphatase staining and activity tests and western blotting (runt-related transcription factor 2, collagen I, osterix and osteopontin), respectively. Immunofluorescence and western blotting were performed to measure the expression levels of hypoxia-inducible factor-1α, pro-fission dynamin-related protein 1, mitochondria-related proteins translocase of inner mitochondrial membrane 23 and translocase of outer mitochondrial membrane 20, in addition to those of autophagy markers (p62, LC3II, Beclin-1 and autophagy-related 5). Transmission electron microscopy was also used to image the autophagosomes and mitochondrial morphology. In addition, to study the functional role of FUNDC1, its expression was silenced by liposome-mediated transfection with small interfering RNA into HDPCs. Compared with those in HDPCs cultured under normoxic conditions (21% O 2 ), the ability of autophagy in HDPCs cultured under hypoxic conditions for 18 h was markedly increased, whilst the proliferation, migration and odontoblastic differentiation were also enhanced. Increased numbers of autophagosomes could also be observed in the hypoxic group. However, FUNDC1 knockdown in HDPCs reversed the aforementioned effects. Overall, data from the present study suggest that hypoxia can promote the proliferation, migration and odontoblastic differentiation of HDPCs, where the underlying mechanism may be associated with the activation of mitophagy downstream of FUNDC1.

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Section: Discussionmentioning

confidence: 99%

Hypoxia‑induced mitophagy regulates proliferation, migration and odontoblastic differentiation of human dental pulp cells through FUN14 domain‑containing 1

et al. 2022

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“…The mammalian mitochondrial membrane protein FUN14 domain containing 1 (FUNDC1) is a mitophagy receptor which interacts with and recruits LC3 to mitochondria for the induction of mitophagy [19]. Several studies have shown that FUNDC1 also exerts vital roles in a wide array of biological events including regulation of mitochondrial dynamics [20], maintenance of mitochondrial calcium homeostasis [21], and cellular plasticity through preservation of oxidative bioenergetics, governance of ROS production and cell proliferation [22], ultimately alleviating mitochondrial damage in multiple diseases [21,23,24]. Nevertheless, the role of FUNDC1 in DOX-induced cardiotoxicity has not been clarified.…”

Section: Introductionmentioning

confidence: 99%

FUNDC1 protects against doxorubicin-induced cardiomyocyte PANoptosis through stabilizing mtDNA via interaction with TUFM

Wang

et al. 2022

Cell Death Dis

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Doxorubicin (DOX) is an effective anthracycline chemotherapeutic anticancer drug with its life-threatening cardiotoxicity severely limiting its clinical application. Mitochondrial damage-induced cardiomyocyte death is considered an essential cue for DOX cardiotoxicity. FUN14 domain containing 1 (FUNDC1) is a mitochondrial membrane protein participating in the regulation of mitochondrial integrity in multiple diseases although its role in DOX cardiomyopathy remains elusive. Here, we examined whether PANoptosis, a novel type of programmed cell death closely associated with mitochondrial damage, was involved in DOX-induced heart injury, and FUNDC1-mediated regulation of cardiomyocyte PANoptosis, if any. FUNDC1 was downregulated in heart tissues in patients with dilated cardiomyopathy (DCM) and DOX-challenged mice. FUNDC1 deficiency aggravated DOX-induced cardiac dysfunction, mitochondrial injury, and cardiomyocyte PANoptosis. Further examination revealed that FUNDC1 countered cytoplasmic release of mitochondrial DNA (mtDNA) and activation of PANoptosome through interaction with mitochondrial Tu translation elongation factor (TUFM), a key factor in the translational expression and repair of mitochondrial DNA, via its 96–133 amino acid domain. TUFM intervention reversed FUNDC1-elicited protection against DOX-induced mtDNA cytosolic release and cardiomyocyte PANoptosis. Our findings shed light toward a beneficial role of FUNDC1 in DOX cardiotoxicity and cardiomyocyte PANoptosis, thus offering therapeutic promises in DOX-induced cardiotoxicity.

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“…The mitophagy process can also be induced by other Parkin-independent mechanisms [24]. FUNDC1 is an OMM localizing protein that can induce mitophagy through the recruitment of MAP1LC3B/LC3B with its LIR motif in mammalian cells [56]. FUNDC1 activity can be regulated by different kinases.…”

Section: Additionalmentioning

confidence: 99%

Mitophagy and Traumatic Brain Injury: Regulatory Mechanisms and Therapeutic Potentials

Luan

Jiang

Luan

et al. 2023

Oxidative Medicine and Cellular Longevity

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Traumatic brain injury (TBI), a kind of external trauma-induced brain function alteration, has posed a financial burden on the public health system. TBI pathogenesis involves a complicated set of events, including primary and secondary injuries that can cause mitochondrial damage. Mitophagy, a process in which defective mitochondria are specifically degraded, segregates and degrades defective mitochondria allowing a healthier mitochondrial network. Mitophagy ensures that mitochondria remain healthy during TBI, determining whether neurons live or die. Mitophagy acts as a critical regulator in maintaining neuronal survival and healthy. This review will discuss the TBI pathophysiology and the consequences of the damage it causes to mitochondria. This review article will explore the mitophagy process, its key factors, and pathways and reveal the role of mitophagy in TBI. Mitophagy will be further recognized as a therapeutic approach in TBI. This review will offer new insights into mitophagy’s role in TBI progression.

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The role of FUNDC1 in mitophagy, mitochondrial dynamics and human diseases

Cited by 43 publications

References 103 publications

Hypoxia‑induced mitophagy regulates proliferation, migration and odontoblastic differentiation of human dental pulp cells through FUN14 domain‑containing 1

Hypoxia‑induced mitophagy regulates proliferation, migration and odontoblastic differentiation of human dental pulp cells through FUN14 domain‑containing 1

FUNDC1 protects against doxorubicin-induced cardiomyocyte PANoptosis through stabilizing mtDNA via interaction with TUFM

Mitophagy and Traumatic Brain Injury: Regulatory Mechanisms and Therapeutic Potentials

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