Exploring the Assembly and Function of the Caf4 Complex and its Role in Mitochondrial Fission

University of Central Arkansas

Abstract

            Mitochondria are the powerhouse of the cell, producing the bulk of the ATP energy necessary for cellular function.  The production of this ATP energy is dependent upon the maintenance of a specialized mitochondrial structure.  Textbooks often simplistically present this structure to look like a jelly bean; however, mitochondria are actually tubular and highly branched (Fig. 1 center).  This specialized tubular structure is maintained by complementary fusion and fission events during which two mitochondria merge into one, or one mitochondrion divides into two, respectively.  These events must be balanced because too much of either fission or fusion can alter the structure of the mitochondria (Fig. 1 left and right), potentially resulting in loss of function and leading to diseases such as dominant optic atrophy, a disease causing childhood blindness. 

To understand the regulation of mitochondrial structure this project focuses on a recently identified protein – Caf4 – and its role in mitochondrial fission.  Three proteins, Dnm1, Mdv1, and Fis1 mediate the physical division of the mitochondrial tubule.  While some of the steps that take place to mediate the actual division event are well understood, it is not known what instructs the mitochondria to divide.  We hypothesize that Caf4 may transmit this signal or instruction to the other proteins. Using fluorescent microscopy we propose to determine Caf4’s function in mitochondrial division, specifically determining if Caf4 instructs Dnm1, Mdv1, and Fis1 to activate.  Understanding Caf4’s function in mitochondrial division will provide valuable insight into how the regulation of mitochondrial structure affects mitochondrial function and, in turn, help us understand mitochondrial diseases.

It is expected that this research project will provide me with the skills necessary to bring more extensive studies to the University of Central Arkansas where undergraduates may participate.  In addition, this project is vital to the long term development of my research program at UCA.  My goal is to attract more undergraduate and graduate students to my lab where additional proposals may be developed to seek long term support to understand how the structure of mitochondria is maintained and to understand the relationship between structure, function and mitochondrial disease.  Additionally, it is expected that the relationship with Dr. Lupashin will develop into a long term collaboration that can lead to multiple principal investigator funding when two kinds of expertise are necessary to complete a project.

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