The Detrimental Effect of Mitochondrial Dysfunction On The Onset Of ATTR Amyloidosis

Abstract

Transthyretin amyloidosis (ATTR) is a progressive and rare disease that is caused by a buildup of amyloid deposits of misfolded transthyretin (TTR) proteins in vital body organs such as the heart. Hepatocytes in the liver are the primary producers of these proteins. Groups of abnormal and misfolded TTR proteins called fibrils build up in the heart’s left ventricle causing difficulty in pumping blood to the rest of the body. The endoplasmic reticulum (ER) consists of a network of membranes in a cell’s cytoplasm that is the location of protein folding, and its dysfunction is implicated in ATTR pathogenesis. ER stress occurs when some factor leads to the accumulation of misfolded proteins. When stress in the ER increases, it can lead to energy depletion in the mitochondria. 

Mitochondria are membrane-bound organelles that generate chemical energy that the cell needs to function in the form of adenosine triphosphate (ATP). Mitochondrial dysfunction is a blanket term used to denote aberrant mitochondrial activity. ER stress is known to promote mitochondrial dysfunction and vice versa. However, in the context of ATTR, the link between mitochondrial dysfunction and ER stress is not entirely defined. Our current hypothesis is that mitochondrial dysfunction contributes to ER stress, which is a principal mediator of ATTR. Herein we will discuss the mechanistic links between ER stress and mitochondrial dysfunction in ATTR pathogenesis.