Protein translocation across mitochondrial membranes: what a long, strange trip it is.
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Biological Transport↗
Biomedical subjects
R E Jensen
Publications and source records attributed to R E Jensen.
MMM1 encodes a mitochondrial outer membrane protein essential for establishing and maintaining the structure of yeast mitochondria.
In the yeast Saccharomyces cerevisiae, mitochondria are elongated organelles which form a reticulum around the cell periphery. To determine the mechanism by which mitochondrial shape is established and maintained, we screened yeast mutants for those defective in mitochondrial morphology. One of these mutants, mmm1, is temperature-sensitive for the external shape of its mitochondria. At the restrictive temperature, elongated mitochondria appear to quickly collapse into large, spherical organelles. Upon return to the permissive temperature, wild-type mitochondrial structure is restored. The morphology of other cellular organelles is not affected in mmm1 mutants, and mmm1 does not disrupt normal actin or tubulin organization. Cells disrupted in the MMM1 gene are inviable when grown on nonfermentable carbon sources and show abnormal mitochondrial morphology at all temperatures. The lethality of mmm1 mutants appears to result from the inability to segregate the aberrant-shaped mitochondria into daughter cells. Mitochondrial structure is therefore important for normal cell function. Mmm1p is located in the mitochondrial outer membrane, with a large carboxyl-terminal domain facing the cytosol. We propose that Mmm1p maintains mitochondria in an elongated shape by attaching the mitochondrion to an external framework, such as the cytoskeleton.
Amino Acid Sequence↗
SMS1, a high-copy suppressor of the yeast mas6 mutant, encodes an essential inner membrane protein required for mitochondrial protein import.
MAS6 encodes an essential inner membrane protein required for mitochondrial protein import in the yeast Saccharomyces cerevisiae (Emtage and Jensen, 1993). To identify new inner membrane import components, we isolated a high-copy suppressor (SMS1) of the mas6-1 mutant. SMS1 encodes a 16.5-kDa protein that contains several potential membrane-spanning domains. The Sms1 protein is homologous to the carboxyl-terminal domain of the Mas6 protein. Like Mas6p, Sms1p is located in the mitochondrial inner membrane and is an essential protein. Depletion of Sms1p from cells causes defects in the import of several mitochondrial precursor proteins, suggesting that Sms1p is a new inner membrane import component. Our observations raise the possibility that Sms1p and Mas6p act together to translocate proteins across the inner membrane.
Amino Acid Sequence↗
A comparison of contact pressures in tibial and patellar total knee components before and after service in vivo.
Laboratory testing of total knee components indicates that many designs produce contact stresses that exceed the yield strength of ultra-high molecular weight polyethylenes (UHMWPEs). It is often assumed that the polyethylene component will creep and wear to become more conforming over time, thus reducing these stresses. To test this theory, retrieved polyethylene tibial and patellar components, which showed signs of increased contact area through in vivo deformation, were tested for contact stress against matching components using Fuji Prescale pressure-sensitive film. The results showed an inverse relationship between initial conformity and in vivo changes in contact stress. More conforming devices showed little or no change in contact stress, and less conforming components showed small decreases in contact stress as a result of creep and wear. Even with these changes, however, the contact stresses for nonconforming designs remained well above those for the more conforming devices as well as the uniaxial yield strength of UHMWPE.
Humans↗
The correlation between fusion defects and damage in tibial polyethylene bearings.
Recent reports of fatigue failures of polyethylene tibial and patellar components have led to investigation of the role of design and material properties in these failures. Earlier investigations, concluding that high contact stress designs suffered greater damage in service, could not account for some of the fatigue failures. The current study hypothesizes that this failure is related to variations in the material properties of the polyethylene due to incomplete consolidation of the powder during manufacture, resulting in fusion defects. Retrieved polyethylene components and samples of polyethylene stock were examined to gain insight into the relationship between fusion defects, component failure, material forming processes, and powder grade. Statistically significant correlations (p < 0.05) were observed between the extent of defects and cracking, delamination, total wear damage, and duration in vivo. These correlations indicate that components manufactured from material with fusion defects may be less resistant to fatigue than components formed of fully consolidated material.
Acetabulum↗
Mas6p can be cross-linked to an arrested precursor and interacts with other proteins during mitochondrial protein import.
Mas6p is an integral membrane protein of the yeast mitochondrial inner membrane, which is essential for mitochondrial protein import (1). To determine whether Mas6p is directly involved in recognizing precursors or translocating them across the inner membrane, we asked if Mas6p was in close proximity to precursor proteins being imported into mitochondria. We report here that Mas6p can be chemically cross-linked to an imported protein arrested in transit through the mitochondrial inner membrane. Antiserum to Mas6p specifically immunoprecipitates one of several different mitochondrial proteins that are cross-linked to blocked precursors. Our results strongly suggest that Mas6p physically interacts with precursors during their translocation into the matrix. In addition, at least two other mitochondrial proteins that are each cross-linked to arrested precursors can be coimmunoprecipitated along with Mas6p under non-denaturing conditions. These observations provide evidence for a complex of proteins including Mas6p, each of which interacts with mitochondrial precursors during import.
Base Sequence↗
Loss of hydroxyapatite coating on retrieved, total hip components.
The goal of this study was to examine the early retrievals of hydroxyapatite-(HA) coated hip prostheses to assess evidence of osteoconductivity, resorption of HA, and the integrity of the HA/implant bond. Six retrieved HA-coated hip prostheses (3 femoral hip stems, 3 acetabular cups) were analyzed for the amount of bone ongrowth or ingrowth of the HA-coated surface and the extent to which the coating was still present after in vivo service. The examination of these six HA-coated prostheses indicates that HA appeared to be osteoconductive. There was evidence of debonding of HA from the smooth-surfaced femoral prosthesis, although that may have been a result of the extraction process. The five plasma-spray surfaced, HA-coated prostheses showed evidence of considerable loss of the HA coating at the time of receipt in the authors' laboratory, although it is was not possible to determine the cause of the loss of coating.
Durapatite↗
MAS6 encodes an essential inner membrane component of the yeast mitochondrial protein import pathway.
To identify new components that mediate mitochondrial protein import, we analyzed mas6, an import mutant in the yeast Saccharomyces cerevisiae. mas6 mutants are temperature sensitive for viability, and accumulate mitochondrial precursor proteins at the restrictive temperature. We show that mas6 does not correspond to any of the presently identified import mutants, and we find that mitochondria isolated from mas6 mutants are defective at an early stage of the mitochondrial protein import pathway. MAS6 encodes a 23-kD protein that contains several potential membrane spanning domains, and yeast strains disrupted for MAS6 are inviable at all temperatures and on all carbon sources. The Mas6 protein is located in the mitochondrial inner membrane and cannot be extracted from the membrane by alkali treatment. Antibodies to the Mas6 protein inhibit import into isolated mitochondria, but only when the outer membrane has been disrupted by osmotic shock. Mas6p therefore represents an essential import component located in the mitochondrial inner membrane.
Amino Acid Sequence↗
Interfaces between host and uncemented femoral hip prostheses.
The authors analyzed 200 uncemented hip prostheses that were retrieved. They determined the type and extent of host-implant interfaces, but found little correlation between subjective pain relief and the histology of the interfaces. Wear debris, bone resorption and looseness were related to pain, although even with these the relationship was not statistically significant.
Alloys↗
Failure of a well-fixed bone-ingrown titanium hip prosthesis.
A cementless titanium femoral stem was revised 5 years after implantation because of acute pain and progressive osteolysis. Substantial amounts of titanium and polyethylene wear debris were found in the surrounding tissues. Multiple sources of this debris were found as well as detachment of titanium fiber-mesh pads from the body of the femoral stem.
Adult↗
Mutations in a 19-amino-acid hydrophobic region of the yeast cytochrome c1 presequence prevent sorting to the mitochondrial intermembrane space.
Most mitochondrial proteins destined for the intermembrane space (IMS) carry in their presequence information for localization to the IMS in addition to information for their import. By selecting for mutants in the yeast Saccharomyces cerevisiae that mislocalize an IMS-targeted fusion protein, we identified mutations in the IMS sorting signal of the cytochrome c1 protein. Amino acid substitutions or deletions in a stretch of 19 hydrophobic amino acids of the cytochrome c1 presequence resulted in accumulation of the intermediate form of the cytochrome c1 protein in the matrix. In some cases, the accumulated intermediate appeared to be slowly exported from the matrix, across the inner membrane to the IMS. Our results support the hypothesis that the cytochrome c1 precursor is normally imported completely into the matrix and then exported to the IMS.
Amino Acid Sequence↗
Corrosion between the components of modular femoral hip prostheses.
We studied the tapered interface between the head and the neck of 139 modular femoral components of hip prostheses which had been removed for a variety of reasons. In 91 the same alloy had been used for the head and the stem; none of them showed evidence of corrosion. In contrast, there was definite corrosion in 25 of the 48 prostheses in which the stem was of titanium alloy and the head of cobalt-chrome. This corrosion was time-dependent: no specimens were corroded after less than nine months in the body, but all which had been in place for more than 40 months were damaged. We discuss the factors which may influence the rate of these changes and present evidence that they were due to galvanically-accelerated crevice corrosion, which was undetected in previous laboratory testing of this type of prosthesis.
Age Factors↗
Mechanisms of failure of modular prostheses.
The expectations of wear and longevity of total hip components are based in large part on Charnley's early work. The evolution of the total hip from the one-piece, all-polyethylene acetabular component and fixed-head femoral component to the myriad of parts that comprise many of today's total hip designs has brought with it an array of potential mechanisms for failure that were not present in the earlier design. The risk/benefit ratio of these new designs may need to be reevaluated based on the additional mechanisms for failure that they provide. One hundred eleven acetabular hip prostheses and 139 femoral prostheses, all of modular configuration, retrieved by surgeons in the field, and sent for histologic examination, were analyzed for this study. A number of component characteristics were found to be correlated to early failure. These included acetabular designs with thin polyethylene bearings, poor fixation of the polyethylene to the metal shell, and geometries that permitted a moment to be applied to the bearing insert, tending to cause it to rotate in the metal shell. Modular femoral components were observed to be susceptible to corrosion, with titanium-alloy stems mated to cast cobalt-alloy heads at greatest risk attributable to a galvanic effect. All modular connections of femoral and acetabular components are at risk for disassociation and fretting; therefore, clever design and precision machining are necessary to produce prostheses in which the benefits of modularity exceed the risks.
Acetabulum↗
Putting the HO gene to work: practical uses for mating-type switching.
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Base Sequence↗
Corrosion at the interface of cobalt-alloy heads on titanium-alloy stems.
The combination of a cobalt-alloy head on a titanium-alloy femoral hip stem is widely accepted for press-fit and biologic fixation applications. Examination of 30 components retrieved at periods of 0.5 to 66.9 months for histologic examination of tissue ingrowth revealed that 56.6% of the tapered connections between head and stem showed evidence of crevice corrosion leading to concerns of metal ion release and the potential failure of head to stem fixation.
Adult↗
All-polyethylene patellar components are not the answer.
Recent reports of the high incidence of polyethylene failure of metal-backed patellar components have rekindled the interest in cemented, all-polyethylene designs. One hundred four retrieved patellar components of metal-backed and all-polyethylene designs were analyzed for wear. Additionally, patellofemoral contact stress as a function of flexion angle was measured for unused components using pressure-sensitive Fuji film. Significant wear (2+ on a 0-3 scale) was seen in 65% of metal-backed designs and in 78% of all-polyethylene components. Severe wear (3) was seen in 44% of all-polyethylene components and in 39% of metal-backed devices. The incidence of severe wear (3) of congruent designs was statistically significantly lower than that of the noncongruent designs. Contact stress analysis confirmed that dome-type geometries typically resulted in stresses that exceed the yield strength of the polyethylene, whereas the more congruent geometries generated significantly reduced stress levels.
Biomechanical Phenomena↗
Analysis of the failure of 122 polyethylene inserts from uncemented tibial knee components.
The extent of wear of retrieved, polyethylene tibial components appears to be related to design. To test this observation, 122 tibial inserts were graded for wear, and new components of several designs were tested for contact stress using Fuji film. Finite element analysis provided insight into subsurface stresses. Significant wear was seen in 61.5% of the tibial inserts examined. The presence of unconsolidated polymer powder was seen in 44% of the tibial inserts and was found to be statistically correlated with severe wear of the articulating surface. Contact stress in several noncongruent designs was found to exceed the yield strength of polyethylene. There was a positive correlation between the intensity of wear and the level of contact stress, with noncongruent designs having greater wear than fully congruent geometries. In the noncongruent designs, the thinner polyethylene components showed greater wear than thicker polyethylene inserts of the same design.
Corrosion↗
Advances in implant-bone interface.
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Animals↗