MCL-1 is an essential BCL-2 family member that promotes the survival of multiple cellular lineages, but its role in cardiac muscle has remained unclear. Here, we have demonstrated that cardiac-specific ablation of Mcl-1 results in a rapidly fatal, dilated cardiomyopathy preceded by loss of myofibrils and cardiac contractility, abnormal mitochondria ultrastructure, defective mitochondrial respiration, and impaired autophagy. Genetic ablation of both pro-apoptotic effectors (Bax and Bak) could largely rescue the lethality and impaired cardiac function induced by Mcl-1 deletion. However, Mcl-1-, Bax-, and Bak-deficient hearts still revealed mitochondrial ultrastructural abnormalities and displayed deficient mitochondrial respiration, and are hypersensitive to chronic isoproterenol challenge. Together, these studies indicate that MCL-1 functions beyond merely blocking cardiomyocyte death and suggest that in myocardium, MCL-1 also facilitates normal mitochondrial function. These findings are important, as overexpression MCL-1 in the heart could be a potential strategy to overcome cardiac injury and promote efficient mitochondrial function and would be beneficial to human health. Of equal importance, specific MCL-1-inhibiting therapeutics that has been proposed to treat cancer may result in unexpected cardiac toxicity; it may be necessary to take this possible side effect into account during MCL-1 inhibitor development.
","abstract_html":"<p>MCL-1 is an essential BCL-2 family member that promotes the survival of multiple cellular lineages, but its role in cardiac muscle has remained unclear. Here, we have demonstrated that cardiac-specific ablation of Mcl-1 results in a rapidly fatal, dilated cardiomyopathy preceded by loss of myofibrils and cardiac contractility, abnormal mitochondria ultrastructure, defective mitochondrial respiration, and impaired autophagy. Genetic ablation of both pro-apoptotic effectors (Bax and Bak) could largely rescue the lethality and impaired cardiac function induced by Mcl-1 deletion. However, Mcl-1-, Bax-, and Bak-deficient hearts still revealed mitochondrial ultrastructural abnormalities and displayed deficient mitochondrial respiration, and are hypersensitive to chronic isoproterenol challenge. Together, these studies indicate that MCL-1 functions beyond merely blocking cardiomyocyte death and suggest that in myocardium, MCL-1 also facilitates normal mitochondrial function. These findings are important, as overexpression MCL-1 in the heart could be a potential strategy to overcome cardiac injury and promote efficient mitochondrial function and would be beneficial to human health. Of equal importance, specific MCL-1-inhibiting therapeutics that has been proposed to treat cancer may result in unexpected cardiac toxicity; it may be necessary to take this possible side effect into account during MCL-1 inhibitor development.</p>","abstract_has_math":false,"creators":["Wang, Xi"],"institution":null,"degree_name":"Doctor of Philosophy (PhD)","degree_level":"Dissertation","degree_discipline":"Biomedical Sciences","degree_department":null,"school":null,"contributors":["Joseph T. Opferman, Ph.D."],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2014,"date_issued":"2014-12-01T08:00:00Z","date_published":"2014-12-01T08:00:00Z","updated_at":"2026-07-24T05:00:23Z","subjects":["apoptosis","BCL-2","heart failure","MCL-1","mitochondria","Cardiovascular Diseases","Diseases","Medical Genetics","Medical Sciences","Medicine and Health Sciences"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://dc.uthsc.edu/dissertations/368","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Joseph T. Opferman, Ph.D."]},{"key":"dc:creator","label":"Author","values":["Wang, Xi"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.available","label":"Dc Date Available","values":["2016-06-22T07:00:00Z"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Biomedical Sciences"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["apoptosis","BCL-2","heart failure","MCL-1","mitochondria","Cardiovascular Diseases","Diseases","Medical Genetics","Medical Sciences","Medicine and Health Sciences"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://dc.uthsc.edu/dissertations/368"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["MCL-1 is an essential BCL-2 family member that promotes the survival of multiple cellular lineages, but its role in cardiac muscle has remained unclear. Here, we have demonstrated that cardiac-specific ablation of Mcl-1 results in a rapidly fatal, dilated cardiomyopathy preceded by loss of myofibrils and cardiac contractility, abnormal mitochondria ultrastructure, defective mitochondrial respiration, and impaired autophagy. Genetic ablation of both pro-apoptotic effectors (Bax and Bak) could largely rescue the lethality and impaired cardiac function induced by Mcl-1 deletion. However, Mcl-1-, Bax-, and Bak-deficient hearts still revealed mitochondrial ultrastructural abnormalities and displayed deficient mitochondrial respiration, and are hypersensitive to chronic isoproterenol challenge. Together, these studies indicate that MCL-1 functions beyond merely blocking cardiomyocyte death and suggest that in myocardium, MCL-1 also facilitates normal mitochondrial function. These findings are important, as overexpression MCL-1 in the heart could be a potential strategy to overcome cardiac injury and promote efficient mitochondrial function and would be beneficial to human health. Of equal importance, specific MCL-1-inhibiting therapeutics that has been proposed to treat cancer may result in unexpected cardiac toxicity; it may be necessary to take this possible side effect into account during MCL-1 inhibitor development.
"]},{"key":"dc:title","label":"Title","values":["The Role of MCL-1 in the Heart: Gateway from Life to Death"]}]}],"canonical_facts":{"dc:contributor":["Joseph T. Opferman, Ph.D."],"dc:creator":["Wang, Xi"],"dc:date.available":["2016-06-22T07:00:00Z"],"dc:description.abstract":["MCL-1 is an essential BCL-2 family member that promotes the survival of multiple cellular lineages, but its role in cardiac muscle has remained unclear. Here, we have demonstrated that cardiac-specific ablation of Mcl-1 results in a rapidly fatal, dilated cardiomyopathy preceded by loss of myofibrils and cardiac contractility, abnormal mitochondria ultrastructure, defective mitochondrial respiration, and impaired autophagy. Genetic ablation of both pro-apoptotic effectors (Bax and Bak) could largely rescue the lethality and impaired cardiac function induced by Mcl-1 deletion. However, Mcl-1-, Bax-, and Bak-deficient hearts still revealed mitochondrial ultrastructural abnormalities and displayed deficient mitochondrial respiration, and are hypersensitive to chronic isoproterenol challenge. Together, these studies indicate that MCL-1 functions beyond merely blocking cardiomyocyte death and suggest that in myocardium, MCL-1 also facilitates normal mitochondrial function. These findings are important, as overexpression MCL-1 in the heart could be a potential strategy to overcome cardiac injury and promote efficient mitochondrial function and would be beneficial to human health. Of equal importance, specific MCL-1-inhibiting therapeutics that has been proposed to treat cancer may result in unexpected cardiac toxicity; it may be necessary to take this possible side effect into account during MCL-1 inhibitor development.
"],"dc:identifier":["https://dc.uthsc.edu/dissertations/368"],"dc:subject":["apoptosis","BCL-2","heart failure","MCL-1","mitochondria","Cardiovascular Diseases","Diseases","Medical Genetics","Medical Sciences","Medicine and Health Sciences"],"dc:title":["The Role of MCL-1 in the Heart: Gateway from Life to Death"],"thesis:degree_discipline":["Biomedical Sciences"],"thesis:degree_level":["Dissertation"],"thesis:degree_name":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-24T05:00:23Z"}