Human apolipoprotein L1 interferes with mitochondrial function in Saccharomyces cerevisiae

Abstract

To the best of our knowledge, the vertebrate apolipoprotein l (aPol) family has not previously been ascribed to any definite pathophysiological function, although the conserved BH3 protein domain suggests a role in programmed cell death or an interference with mitochondrial processes. in the present study, the human aPol1 was expressed in the yeast Saccharomyces cerevisiae in order to determine the molecular action of aPol1. aPol1 inhibited cell proliferation in a non-fermentable carbon source, such as glycerol, while it had no effect on proliferation in fermentable carbon sources, such as galactose. aPol1, expressed in yeast, is localized in the mitochondrial fraction, as determined via western blotting. aPol1 induced a loss of mitochondrial function, demonstrated by a loss of respiratory index, and mitochondrial membrane potential. Green fluorescent protein tagging of mitochondrial protein revealed that aPol1 was associated with abnormal mitochondrial and lysosomal morphologies, observed by a loss of the normal mitochondrial tubular network. Thus, the results of the present study suggest that aPol1 could be a physiological regulator of mitochondrial function.

Apolipoproteins L1 and L3 control mitochondrial membrane dynamics

“… 40 (3) APOL1 can directly associate with mitochondria. 26 , 27 (4) In APOL1-KO cells, the mitochondrial fission rate is decreased, suggesting that APOL1 absence lowers PI4KB targeting to the mitochondria. (5) In APOL1-KO cells, mitophagosome-endolysosome fusion and poly(I:C)-induced apoptosis are reduced, 11 suggesting that APOL1 absence lowers APOL3 targeting to the mitochondria.…”

“…Both APOL1 and APOL3 bind to the mitochondrion-specific phospholipid cardiolipin, 11 and APOL1 strongly associates with mitochondrial membranes following in vitro incubation 26 or ectopic expression in yeast. 27 Specifically, APOL1 or APOL3 may affect mitochondrial membrane fusion, which involves cardiolipin. 28 Indeed, APOL1 or APOL3 uptake in trypanosomes is linked to increased mitochondrial fusion, 14 , 26 and APOL3 exhibits fusion activity on cardiolipin-rich bacterial membranes.…”

The Janus-faced functions of Apolipoproteins L in membrane dynamics

“…The MAD domain could be involved in APOL1 and APOL3 binding to cardiolipin [ 11 ], the characteristic phospholipid of both bacterial and mitochondrial membranes. Accordingly, APOL1 associates with the mitochondrion when expressed in yeast [ 19 ]. After a long hinge sequence (APOL1 A291-A339; APOL3 A232-T272), a second HC-LZ tandem (HC2-LZ2) characterizes the C-terminal region of both APOLs (APOL1 S342-L392; APOL3 G275-L325).…”