Tian Lab

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This week we profile a recent publication in the Journal of Clinical Investigation from the laboratories of Drs. Rong Tian (pictured, middle row, center) and Jim Bruce at UW.

Can you provide a brief overview of your lab’s current research focus?

Tian lab: Research in the Tian lab focuses on the role of mitochondria and metabolism in human diseases. One special emphasis is to understand metabolic reprograming of the cell during stress response or pathological transition.

Bruce lab: Research in the Bruce lab focuses on technology development and applications to visualize interactome changes that underpin diseases and aging to increase understanding of functional differences that can ultimately benefit human health.

What is the significance of the findings in this publication?

Tian lab: This publication reveals a novel driver of metabolic switch in cardiomyocytes undergoing pathological hypertrophy.  A mitochondrial protein, called Mitochondrial ATPase Inhibitory Factor 1 (ATPIF1), is upregulated in hypertrophied cardiomyocytes.  In collaboration with Jim Bruce’s lab at UW Genome Science department, we found the binding of ATPIF1 with mitochondrial ATP synthase promoted the formation of inactive ATP synthase complex.  This leads to increased production of reactive oxygen species in the mitochondria and ultimately, activation of glycolysis through transcriptional mechanisms. The switch from oxidative ATP production to glycolysis favors cell growth at the expense of energy production. Thus, interaction between ATPIF1 and ATP synthase in the mitochondria toggles anabolic and catabolic metabolism in response to environmental stresses.   

Bruce lab: The CDC estimates 6.2 million adults in the US have heart failure, which is a serious condition whereby the heart is no longer able to provide adequate blood and oxygen to all organs in the body.  To pump blood, the heart requires energy in the form of adenosine triphosphate (ATP) which is the primary bioenergetic currency used in all life processes. Mitochondria are subcellular organelle in heart muscle cells or cardiomyocytes, that produce the ATP required for the heart to provide blood supply.  Since ATP production is decreased in heart failure, the collaborative work described in this publication aimed to identify interactome changes to improve understanding of metabolic alterations involved in decreased ATP production.  The work in this publication revealed for the first time that the interaction of the peptide ATIF1 with the key enzyme that mediates ATP production in mitochondria, ATP synthase, is increased in a pressure overload murine heart failure model.  Previously, ATIF1 was thought only to interact with ATP synthase to inhibit ATP hydrolysis under ischemic conditions.  The interactome quantitation presented in this publication yielded the surprising observation that, under conditions of pressure overload where demand on heart function is high, ATPIF1 interaction with ATP synthase was significantly upregulated.  Moreover, these interactome changes also indicated that the increased ATPIF1 interactions resulted in increased levels of inactive ATP synthase tetramers.   This finding was then explored with a series of ATPIF1 gain- and loss-of-function experiments to reveal an unexpected role of ATIF1 in the switch to glycolytic mitochondrial metabolic pathways in heart failure.  In summary, the findings in this publication hold new significance for ATIF1 function and improved understanding of mitochondrial metabolic regulation in heart failure.      

What are the next steps for this research?

Tian lab: The goal of the lab is to discover mechanisms of metabolic reprogramming and seek therapeutic targets. 

Bruce lab: With the murine model of heart failure we have employed for previous studies, male and female mice exhibit different response to the stress of pressure overload.  Female mice exhibit mild and more variable phenotypic response to pressure overload and therefore, only male mice were used in our previous interactome studies.  However, knowledge of interactome changes that occur in female and the differences from male mice can further reveal which interactome changes are important for heart failure phenotype severity in males or confer protective function in female mice during pressure overload.  Thus, our future studies will include both male and female mice to identify gender-dependent interactome changes during heart failure to further increase understanding of functional changes underlying heart failure pathology. 

If you’d like us to mention your funding sources, please list them.

The work is supported by grants from the NIH and American Heart Association.

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