Mitochondria helped remove protein aggregates from heart cells in mice with inherited cardiomyopathy
Mitochondria helped remove protein aggregates from heart cells in mice with inherited cardiomyopathy
On August 26, an early version of a study describing how heart cells remove protein deposits was published in Circulation Research. The authors showed that a mitochondrion can take up such a protein, after which the cell removes the mitochondrion together with its cargo. In human heart cells, this pathway reduced the number of aggregates. In transgenic mice, it improved cardiac function and survival.
In inherited cardiomyopathy, the R120G variant of CRYAB forms aggregates, which are dense deposits of misfolded proteins. These deposits sequester DESMIN, a structural protein that supports the contractile fibers of heart cells, disrupting their organization.
The authors tested whether cells could remove this cargo through mitophagy, the process by which a cell breaks down a mitochondrion. In isolated mitochondria, R120G-CRYAB remained inside even after the outer membrane had been removed. HSC70, a protein that assists transport, was required for this pathway. When HSC70 levels were reduced in human cardiomyocytes carrying R120G, the cells took longer to relax after contraction.
The researchers then altered mitophagy itself. In mice carrying R120G, reducing TRAF2, a regulator of constitutive mitophagy in cardiac muscle, increased the number of aggregates, weakened left ventricular contraction, and reduced survival. In the converse experiment, the AAV9 viral gene vector delivered additional TRAF2 to heart cells. The mice developed fewer aggregates, DESMIN returned to its usual position within the contractile fibers, and cardiac function and survival improved. PARKIN, another regulator of mitophagy, produced similar changes in aggregate burden and systolic function.
In this inherited mouse model, mitochondria contributed to clearing the cytosol by taking up aggregates, after which the cell broke down the mitochondria together with this cargo. The authors also traced this sequence in cardiomyocytes derived from human induced pluripotent stem cells.