Stomatin-Like Protein 2 Binds Cardiolipin and Regulates Mitochondrial Biogenesis and Function

Abstract

Stomatin-like protein 2 (SLP-2) is a widely expressed mitochondrial inner membrane protein of unknown function. Here we show that human SLP-2 interacts with prohibitin-1 and -2 and binds to the mitochondrial membrane phospholipid cardiolipin. Upregulation of SLP-2 expression increases cardiolipin content and the formation of metabolically active mitochondrial membranes and induces mitochondrial biogenesis. In human T lymphocytes, these events correlate with increased complex I and II activities, increased intracellular ATP stores, and increased resistance to apoptosis through the intrinsic pathway, ultimately enhancing cellular responses. We propose that the function of SLP-2 is to recruit prohibitins to cardiolipin to form cardiolipinenriched microdomains in which electron transport complexes are optimally assembled. Likely through the prohibitin functional interactome, SLP-2 then regulates mitochondrial biogenesis and function.

Stomatin-like Protein 2 Deficiency in T Cells Is Associated with Altered Mitochondrial Respiration and Defective CD4+ T Cell Responses

“…The function of these proteins has been linked to the regulation of assembly and function of multichain receptors (6,(10)(11)(12)(13). In line with this proposed function, we have recently shown that SLP-2 binds cardiolipin (CL) and promotes the formation of specialized CL-enriched microdomains that could facilitate the assembly of protein complexes within mitochondrial membranes (10).…”

“…As the amount of PHB1 in detergentsoluble fractions of control and SLP-2 T-K/O cells was similar, the loss of PHB1 from the insoluble fraction suggested an abnormal compartmentalization in the SLP-2 T-K/O mitochondrial membrane. We have recently shown that SLP-2 not only interacts with PHB but also binds CL, the signature phospholipid linked to detergentinsoluble microdomains of mitochondrial membranes (10). Therefore, the defect in mitochondrial membrane compartmentalization of PHB1 associated with SLP-2 deficiency prompted us to test if the content or distribution of CL was also impaired.…”

“…It is a member of the highly conserved stomatin family, which is composed of stomatin, SLP-1, SLP-2, and SLP-3 (2-7) and as such is part of the SPFH superfamily that also includes prohibitins (PHB), flotillins, and the bacterial proteins HflC and HflK (8,9). The function of these proteins has been linked to the regulation of assembly and function of multichain receptors (6,(10)(11)(12)(13). In line with this proposed function, we have recently shown that SLP-2 binds cardiolipin (CL) and promotes the formation of specialized CL-enriched microdomains that could facilitate the assembly of protein complexes within mitochondrial membranes (10).…”

Immunohistochemical activity of Prohibitin-2 and Stomatin-Like Protein-2 in patients with ulcerative colitis

“…Slp-2 coalesces with cardiolipin, and regulates the optimal assembly of prohibitins and other oxidative enzymes in the mitochondrial inner membrane. Slp-2 is located in the T-cell membrane receptor and modulates immunologic activity (4)(5)(6)(7). Mitochondrial dysfunction is an important pathogenic factor that aggravates oxidative damage in UC.…”

“…Mitochondrial dysfunction is an important pathogenic factor that aggravates oxidative damage in UC. Deficiency of Phb-2 and Slp-2 may lead to mitochondrial dysfunction (2,4,5).…”