By: Richard D. Cummings
Until a few years ago it was believed that mitochondria do not contain glycoproteins. However, mitochondria contain a variant form of the enzyme UDP-GlcNAc: polypeptide O-β-N-acetylglucosaminyltransferase (OGT) that adds O-GlcNAc to Ser/Thr residues of proteins in mitochondria (1,2). There are several reports demonstrating the presence of O-GlcNAcylated glycoproteins in mitochondria (3), but the most extensive may be the many dozens of O-GlcNAcylated proteins associated with the oxidative phosphorylation system (4,5). Alterations in mitochondrial O-GlcNAc glycosylation pathways by deletion of O-GlcNAcase (OGA) causes mitochondria to have reduced size but an overall increase in total mitochondrial numbers and mass (6). Many mitochondrial proteins involved in energy metabolism and many other mitochondrial functions are regulated by O-GlcNAc modifications (7). Inhibition of the removal of O-GlcNAc in mice through administration of the OGA inhibitor thiamet G (TMG) causes reduction of symptoms in a mouse model of Down Syndrome that exhibits hallmarks of Alzheimer’s Disease (8). Also recent studies demonstrate that neuronal O-GlcNAcylation is important to mitochondrial plasticity and overall neuronal activity (9). Loss of the OGT can lead to dysfunctional mitochondrial/endoplasmic reticulum coupling, and cytoskeletal organization in osteoblasts, suggesting a role for mitochondrial O-GlcNAcylated glycoproteins in osteogenesis (10).
In addition to O-GlcNAc modification of mitochondrial glycoproteins, there is growing evidence of other types of glycosylation of mitochondria. Earlier studies demonstrated that mitochondria from the protozoan parasites Leishmania major and Trypanosoma brucei, contain a1,2-fucosyltransferases which are encoded by the mitochondrial genome and which are essential genes (11,12). There are other studies suggesting that glycoproteins containing oligomannose-type N-glycans may be found in mammalian mitochondria and may be derived directly from the ER (13,14) or through other pathways (15), and could also arise by mitochondrial sequestration of ER-misfolded proteins (16). Perhaps such glycosylation is involved in proteostasis, as accumulation of misfolded proteins may impair mitochondrial function. An earlier study had reported that a key glycosylation gene ALG7, involved in N-glycan biosynthesis and adds the first GlcNAc residue to Dol-P-P, is important for optimal mitochondrial function in yeast (17). Interestingly, a recent study reported that the cellular prion protein (PrPC) in a transmembrane form with 2 N-glycans in a mature form occurs in mitochondria of the mouse brain model (18). Other studies using various lectins suggest the presence of N-glycosylated glycoproteins in mitochondria of microglial cells, but the glycoproteins were not identified, although studies are continuing to define the structures of the glycans (19,20). Intriguingly, a recent paper reported the translocation of MGAT1, which is the key enzyme to generate complex N-glycans, into mitochondria, driven by changes in lactate production; this suggests a link in lactate production and protein glycosylation, though no changes in proteins glycosylation were identified (21). Clearly, more studies are needed to resolve questions about N-glycosylated proteins in mitochondria. Thus, while unusual glycosylation of proteins may occur in mitochondria in addition to O-GlcNAc, more studies are needed in that direction to understand their roles in metabolism and energy production.
References
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