8.A.120.  The Mitochondrial StAR-related lipid transfer protein (StAR) Family 

StarD7 is anchored onto the outer mitochondrial membrane through its N-terminal TMS, and the C-terminal START domain may extend into the cytoplasm and shuttle phosphatidyl choline between the ER and the outer mitochondrial membrane at  ER-mitochondrion contact sites (Horibata et al. 2017) (see TC# 1.R.1). Therefore, StarD7 facilitates phosphatidylcholine (PC) transfer to mitochondria and is essential for mitochondrial homeostasis. A  putative TMS, C-terminal to the mitochondria-targeting signal (MTS) sequence at the N-terminus of StarD7 may play an important role. The mature form of StarD7 is integrated into and/or associated with the outer leaflet of the outer mitochondrial membrane. The precursor form of StarD7 is cleaved between Met(76) and Ala(77), and Ala(77) and Ala(78) in the TMS to produce the mature form (Horibata et al. 2017).

MLN64 (metastatic lymph node 64) and MENTHO (MLN64 N-terminal homologue) are two late-endosomal proteins that share a conserved region of four TMSs with three short intervening loops called the MENTAL domain (MLN64 N-terminal domain) (Alpy and Tomasetto 2006). This domain mediates MLN64 and MENTHO homo- and hetero-interactions, targets both proteins to late endosomes and binds cholesterol in vivo. In addition to the MENTAL domain, MLN64 contains a cholesterol-specific START domain [StAR (steroidogenic acute regulatory protein)-related lipid transfer domain]. The START domain is a protein module of approx. 210 residues that binds lipids, including sterols, and is present in 15 distinct proteins in mammals. They may function in cholesterol transport. The MENTAL domain might serve to maintain cholesterol at the membrane of late endosomes prior to its shuttle to cytoplasmic acceptor(s) through the START domain (Alpy and Tomasetto 2006).

The human metastatic lymph node 64 (MLN64) protein is a 4 TMS protein, where residues 52-170 in this 445 aa protein are transmembrane. The Drosophila melanogaster Start1 protein is a homologous 4 TMS protein where residues 62-183 in this 583 aa protein are transmembrane. Roth et al. 2004 proposed that Start1 is a cholesterol transporter.MLN64 transport to the late endosome is regulated by binding to the 14-3-3 protein (TC# 8.A.98.1.1)via a non-canonical binding site (Liapis et al. 2012). Steroid hormone biosynthesis in mitochondria has been reviewed (Miller 2013).

The two proteins, Start1 and MLN64, are homologous to the vertebrate cholesterol-binding steroid acute regulatory protein (STAR)-related lipid transfer domain (START). MLN64 is somehow involved in cholesterol trafficking and/or steroid synthesis. Roth et al. 2004 suggested that Start1 plays a role in the regulation of ecdysteroid synthesis, and expression of Start1 depends on ecdysone. These authors suggested that Start1 is a cholesterol transporter since ecdysteroid is synthesized from cholesterol. Another group, Kennedy et al. 2014  showed that MLN64, mediates endosomal cholesterol transport to mitochondria.

START domains are ~210 aa lipid binding domains implicated in intracellular lipid transport, lipid metabolism and cell signaling (Soccio and Breslow 2003). The human and mouse genomes have 15 genes encoding START domains. The x-ray structures of three such proteins have been solved (see Soccio and Breslow 2003 for a review). The membrane specificity of the human cholesterol transfer protein STARD4 has been deefined (Talandashti et al. 2024).  Targeting STARD4/EGFR axis inhibits growth and overcomes lenvatinib resistance in hepatocellular carcinoma in humans (Liu et al. 2025).