Mcl-1 Differentially Regulates Autophagy in Response to Changes in Energy Status and Mitochondrial Damage

Moyzis, Alexandra G; Lally, Navraj S; Liang, Wenjing; Najor, Rita H.; Gustafsson, Åsa B.

doi:10.3390/cells11091469

Cited by 8 publications

(5 citation statements)

References 42 publications

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“…5 ). These observations parallel studies demonstrating a role for Mcl-1 in regulating autophagy upon mitochondrial stress [ 51 ], and others linking lysosomal membrane permeabilization with MOMP [ 56 , 57 ].…”

Section: Discussionsupporting

confidence: 84%

“…3C, D ). Mcl-1 is a Bcl-2 family member known to correlate with PTC aggressiveness and resistance to BRAFi [ 50 ], and can regulate the clearance of dysfunctional mitochondria [ 51 ]. Western blot analysis revealed higher Mcl-1 expression in MDA-T32 compared to the susceptible MDA-T41 cell line and was maintained when challenged with BRAFi (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Mcl-1 mediates intrinsic resistance to RAF inhibitors in mutant BRAF papillary thyroid carcinoma

Cavallo,

Yo,

Gallant

et al. 2024

Cell Death Discov.

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Papillary thyroid carcinoma (PTC) is the most frequent form of thyroid cancer. PTC commonly presents with mutations of the serine/threonine kinase BRAF (BRAFV600E), which drive ERK1/2 pathway activation to support growth and suppress apoptosis. PTC patients often undergo surgical resection; however, since the average age of PTC patients is under 50, adverse effects associated with prolonged maintenance therapy following total thyroidectomy are a concern. The development of mutant-selective BRAF inhibitors (BRAFi), like vemurafenib, has been efficacious in patients with metastatic melanoma, but the response rate is low for mutant BRAF PTC patients. Here, we assay the therapeutic response of BRAFi in a panel of human PTC cell lines and freshly biopsied patient samples. We observed heterogeneous responses to BRAFi, and multi-omic comparisons between susceptible and resistant mutant BRAF PTC revealed overrepresented stress response pathways and the absence of compensatory RTK activation – features that may underpin innate resistance. Importantly, resistant cell lines and patient samples had increased hallmarks of failed apoptosis; a cellular state defined by sublethal caspase activation and DNA damage. Further analysis suggests that the failed apoptotic phenotypes may have features of “minority mitochondrial outer membrane permeabilization (MOMP)” – a stress-related response characterized by fragmented and porous mitochondria known to contribute to cancer aggressiveness. We found that cells presenting with minority MOMP-like phenotypes are dependent on the apoptotic regulator, Mcl-1, as treatment with the Mcl-1 inhibitor, AZD5991, potently induced cell death in resistant cells. Furthermore, PI3K/AKT inhibitors sensitized resistant cells to BRAFi; an effect that was at least in part associated with reduced Mcl-1 levels. Together, these data implicate minority MOMP as a mechanism associated with intrinsic drug resistance and underscore the benefits of targeting Mcl-1 in mutant BRAF PTC.

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Section: Discussionsupporting

confidence: 84%

Section: Resultsmentioning

confidence: 99%

Mcl-1 mediates intrinsic resistance to RAF inhibitors in mutant BRAF papillary thyroid carcinoma

Cavallo,

Yo,

Gallant

et al. 2024

Cell Death Discov.

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“…However, mutations in the three LIR motifs of MCL-1 do not entirely abrogate mitophagy, suggesting that mechanisms other than the LC3 pathway may also contribute to MCL-1-promoted mitophagy. 141 In addition, the interaction between MCL-1 and BNIP3 increases during the early stage of hypoxia and under FCCP treatment, suggesting that MCL-1 may promote mitophagy through BNIP3. In conclusion, MCL-1 can regulate mitophagy through various pathways.…”

Section: Pathway and Mechanism Of Mitophagymentioning

confidence: 96%

The mitophagy pathway and its implications in human diseases

Wang,

Long,

Hou

et al. 2023

Sig Transduct Target Ther

130

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Mitochondria are dynamic organelles with multiple functions. They participate in necrotic cell death and programmed apoptotic, and are crucial for cell metabolism and survival. Mitophagy serves as a cytoprotective mechanism to remove superfluous or dysfunctional mitochondria and maintain mitochondrial fine-tuning numbers to balance intracellular homeostasis. Growing evidences show that mitophagy, as an acute tissue stress response, plays an important role in maintaining the health of the mitochondrial network. Since the timely removal of abnormal mitochondria is essential for cell survival, cells have evolved a variety of mitophagy pathways to ensure that mitophagy can be activated in time under various environments. A better understanding of the mechanism of mitophagy in various diseases is crucial for the treatment of diseases and therapeutic target design. In this review, we summarize the molecular mechanisms of mitophagy-mediated mitochondrial elimination, how mitophagy maintains mitochondrial homeostasis at the system levels and organ, and what alterations in mitophagy are related to the development of diseases, including neurological, cardiovascular, pulmonary, hepatic, renal disease, etc., in recent advances. Finally, we summarize the potential clinical applications and outline the conditions for mitophagy regulators to enter clinical trials. Research advances in signaling transduction of mitophagy will have an important role in developing new therapeutic strategies for precision medicine.

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“…However, BNIP3 is also involved in Parkin-independent mitophagy. Myeloid cell leukemia-1 (Mcl-1), an anti-apoptotic Bcl-2 member, interacts with BNIP3 to enhance mitophagy in the heart in the presence of energy stress and mitochondrial damage [ 113 ]. Mcl-1 has an LIR motif and acts as an adaptor for BNIP3 to promote mitophagy.…”

Section: Introductionmentioning

confidence: 99%

Mitophagy for cardioprotection

Titus,

Sung,

Zablocki

et al. 2023

Basic Res Cardiol

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Mitochondrial function is maintained by several strictly coordinated mechanisms, collectively termed mitochondrial quality control mechanisms, including fusion and fission, degradation, and biogenesis. As the primary source of energy in cardiomyocytes, mitochondria are the central organelle for maintaining cardiac function. Since adult cardiomyocytes in humans rarely divide, the number of dysfunctional mitochondria cannot easily be diluted through cell division. Thus, efficient degradation of dysfunctional mitochondria is crucial to maintaining cellular function. Mitophagy, a mitochondria specific form of autophagy, is a major mechanism by which damaged or unnecessary mitochondria are targeted and eliminated. Mitophagy is active in cardiomyocytes at baseline and in response to stress, and plays an essential role in maintaining the quality of mitochondria in cardiomyocytes. Mitophagy is mediated through multiple mechanisms in the heart, and each of these mechanisms can partially compensate for the loss of another mechanism. However, insufficient levels of mitophagy eventually lead to mitochondrial dysfunction and the development of heart failure. In this review, we discuss the molecular mechanisms of mitophagy in the heart and the role of mitophagy in cardiac pathophysiology, with the focus on recent findings in the field.

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Mcl-1 Differentially Regulates Autophagy in Response to Changes in Energy Status and Mitochondrial Damage

Cited by 8 publications

References 42 publications

Mcl-1 mediates intrinsic resistance to RAF inhibitors in mutant BRAF papillary thyroid carcinoma

Mcl-1 mediates intrinsic resistance to RAF inhibitors in mutant BRAF papillary thyroid carcinoma

The mitophagy pathway and its implications in human diseases

Mitophagy for cardioprotection

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