RESUMO
Signaling diversity and subsequent complexity in higher eukaryotes is partially explained by one gene encoding a polypeptide with multiple biochemical functions in different cellular contexts. For example, mouse double minute 2 (MDM2) is functionally characterized as both an oncogene and a tumor suppressor, yet this dual classification confounds the cell biology and clinical literatures. Identified via complementary biochemical, organellar, and cellular approaches, we report that MDM2 negatively regulates NADH:ubiquinone oxidoreductase 75 kDa Fe-S protein 1 (NDUFS1), leading to decreased mitochondrial respiration, marked oxidative stress, and commitment to the mitochondrial pathway of apoptosis. MDM2 directly binds and sequesters NDUFS1, preventing its mitochondrial localization and ultimately causing complex I and supercomplex destabilization and inefficiency of oxidative phosphorylation. The MDM2 amino-terminal region is sufficient to bind NDUFS1, alter supercomplex assembly, and induce apoptosis. Finally, this pathway is independent of p53, and several mitochondrial phenotypes are observed in Drosophila and murine models expressing transgenic Mdm2.
Assuntos
Mitocôndrias/metabolismo , NADH Desidrogenase/genética , Estresse Oxidativo/genética , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteína Supressora de Tumor p53/genética , Células A549 , Animais , Apoptose/genética , Respiração Celular/genética , Citosol/metabolismo , Drosophila melanogaster/genética , Complexo I de Transporte de Elétrons/genética , Humanos , Camundongos , Camundongos Transgênicos , Mitocôndrias/genética , Transdução de Sinais/genéticaRESUMO
CONTEXT: Parkinson's disease (PD) is a neurodegenerative disease that leads to impaired motor and non-motor function in patients. PD is non-curative and gradually reduces quality of life, leading patients to seek treatment for symptom management. Osteopathic manipulative treatment (OMT) applies the biomechanical, neurologic, circulatory, metabolic, and psychosocial models in approaching and treating the major symptomatology of PD patients. OBJECTIVES: This article evaluates the literature published in the past 10 years analyzing evidence on OMT and its functional application on gait, balance, motor function, bradykinesia, and autonomic dysfunctions, and to identify promising avenues for further investigation. METHODS: The authors obtained studies from the research databases MEDLINE/PubMed, ScienceDaily, and EBSCO, as well as the Journal of American Osteopathic Association's published archives. Searches were conducted in December 2020 utilizing the search phrases "OMM" (osteopathic manipulative medicine), "OMT," "osteopathic," "Parkinson Disease," "manual therapy," "physical therapy," "training," "autonomics," "gait," and "balance." Articles published between 2010 and 2021 including subjects with Parkinson's disease and the use of OMT or any other form of manual therapy were included. Five authors independently performed literature searches and methodically resolved any disagreements over article selection together. RESULTS: There were a total of 10,064 hits, from which 53 articles were considered, and five articles were selected based on the criteria. CONCLUSIONS: The progressive nature of PD places symptom management on the forefront of maintaining patients' quality of life. OMT has demonstrated the greatest efficacy on managing motor-related and neurologic symptoms and assists in treating the greater prevalence of somatic dysfunctions that arise from the disease. Research in this field remains limited and should be the target of future research.