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Issue: Issue 4 (2017) – Supplement 3

Review Article

The ups and downs of cellular stress: the “MAM hypothesis” for Bipolar disorder pathophysiology

Ana Catarina Pereira, Rosa Resende, Sofia Morais, Nuno Madeira, and Claudia Fragão Pereira
Mental health problems constitute the largest single source of world economic burden, with an estimated global cost greater than cardiovascular disease, cancer or diabetes individually. In the European Union mental disorders affect millions of people and these numbers are expected to rise as result of Europe's ageing population. Given the biological causes of many of these disorders, most studies focus on their molecular basis. Bipolar disorder (BD) is characterized by mood swings between depression and mania resulting in cognitive and functional impairments that require lifetime treatment. Recurrent mood episodes, residual symptoms, functional impairment, psychosocial disability with high rates of divorce, unemployment, drug abuse and suicide attempting, and significant medical comorbidities such as metabolic and cardiovascular diseases cannot be efficiently controlled even with proper use of current treatments. Moreover, delayed diagnosis/misdiagnosis is frequent because reliable biomarkers are absent. Therefore, a better understanding of BD pathophysiology is a prerequisite for the design of new drugs and their implementation in clinical practice as well as to develop biomarkers for a more accurate and earlier diagnosis and/or evaluation of therapeutic response. This review summarises the association between decreased cellular resilience towards stress and BD. Since the key stress-response mediator Mitochondria-Associated Membranes (MAMs) modulate several BD relevant processes such as mitochondrial dysfunction and oxidative stress, Ca2+ deregulation and cytoskeleton abnormalities, endoplasmic reticulum stress responses, loss of proteostasis and inflammasome activation, we propose the “MAM hypothesis” for BD pathophysiology. Targeting MAM-associated signaling pathways can be a promising investigation avenue to identify novel therapeutic strategies.

Keywords: Bipolar disorder, Endoplasmic reticulum, Mitochondria, Mitochondria-associated membranes, Cellular resilience, Cellular stress, Plasticity.

Special Issue on the Neurobiology of Mental Illness

International Journal of Clinical Neurosciences and Mental Health 2017; 4(Suppl. 3):S04
DOI: https://doi.org/10.21035/ijcnmh.2017.4(Suppl.3).S04
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