p21WAF1 is required for butyrate-mediated growth inhibition of human colon cancer cells

A diet high in fiber is associated with a decreased incidence and growth of colon cancers. Butyrate, a four-carbon short-chain fatty acid product of fiber fermentation within the colon, appears to mediate these salutary effects. We sought to determine the molecular mechanism by which butyrate mediates growth inhibition of colonic cancer cells and thereby to elucidate the molecular link between a high-fiber diet and the arrest of colon carcinogenesis. We show that concomitant with growth arrest, butyrate induces p21 mRNA expression in an immediate-early fashion, through transactivation of a promoter cis-element(s) located within 1.4 kb of the transcriptional start site, independent of p53 binding. Studies using the specific histone hyperacetylating agent, trichostatin A, and histone deacetylase 1 indicate that growth arrest and p21 induction occur through a mechanism involving histone hyperacetylation. We show the critical importance of p21 in butyrate-mediated growth arrest by first confirming that stable overexpression of the p21 gene is able to cause growth arrest in the human colon carcinoma cell line, HT-29. Furthermore, using p21-deleted HCT116 human colon carcinoma cells, we provide convincing evidence that p21 is required for growth arrest to occur in response to histone hyperacetylation, but not for serum starvation nor postconfluent growth. Thus, p21 appears to be a critical effector of butyrate-induced growth arrest in colonic cancer cells, and may be an important molecular link between a high-fiber diet and the prevention of colon carcinogenesis.

Natural trans-splicing in carnitine octanoyltransferase pre-mRNAs in rat liver

Carnitine octanoyltransferase (COT) transports medium-chain fatty acids through the peroxisome. During isolation of a COT clone from a rat liver library, a cDNA in which exon 2 was repeated, was characterized. Reverse transcription-PCR amplifications of total RNAs from rat liver showed a three-band pattern. Sequencing of the fragments revealed that, in addition to the canonical exon organization, previously reported [Choi, S. J. et al. (1995) Biochim. Biophys. Acta 1264, 215–222], there were two other forms in which exon 2 or exons 2 and 3 were repeated. The possibility of this exonic repetition in the COT gene was ruled out by genomic Southern blot. To study the gene expression, we analyzed RNA transcripts by Northern blot after RNase H digestion of total RNA. Three different transcripts were observed. Splicing experiments also were carried out in vitro with different constructs that contain exon 2 plus the 5′ or the 3′ adjacent intron sequences. Our results indicate that accurate joining of two exons 2 occurs by a trans-splicing mechanism, confirming the potential of these structures for this process in nature. The trans-splicing can be explained by the presence of three exon-enhancer sequences in exon 2. Analysis by Western blot of the COT proteins by using specific antibodies showed that two proteins corresponding to the expected Mr are present in rat peroxisomes. This is the first time that a natural trans-splicing reaction has been demonstrated in mammalian cells.

A mouse model for X-linked adrenoleukodystrophy

X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder with impaired β-oxidation of very long chain fatty acids (VLCFAs) and reduced function of peroxisomal very long chain fatty acyl-CoA synthetase (VLCS) that leads to severe and progressive neurological disability. The X-ALD gene, identified by positional cloning, encodes a peroxisomal membrane protein (adrenoleukodystrophy protein; ALDP) that belongs to the ATP binding cassette transporter protein superfamily. Mutational analyses and functional studies of the X-ALD gene confirm that it and not VLCS is the gene responsible for X-ALD. Its role in the β-oxidation of VLCFAs and its effect on the function of VLCS are unclear. The complex pathology of X-ALD and the extreme variability of its clinical phenotypes are also unexplained. To facilitate understanding of X-ALD pathophysiology, we developed an X-ALD mouse model by gene targeting. The X-ALD mouse exhibits reduced β-oxidation of VLCFAs, resulting in significantly elevated levels of saturated VLCFAs in total lipids from all tissues measured and in cholesterol esters from adrenal glands. Lipid cleft inclusions were observed in adrenocortical cells of X-ALD mice under the electron microscope. No neurological involvement has been detected in X-ALD mice up to 6 months. We conclude that X-ALD mice exhibit biochemical defects equivalent to those found in human X-ALD and thus provide an experimental system for testing therapeutic intervention.

Study of the 3-Hydroxy Eicosanoyl-Coenzyme A Dehydratase and (E)-2,3 Enoyl-Coenzyme A Reductase Involved in Acyl-Coenzyme A Elongation in Etiolated Leek Seedlings1

(R,S)-[1-14C]3-Hydroxy eicosanoyl-coenzyme A (CoA) has been chemically synthesized to study the 3-hydroxy acyl-CoA dehydratase involved in the acyl-CoA elongase of etiolated leek (Allium porrum L.) seedling microsomes. 3-Hydroxy eicosanoyl-CoA (3-OH C20:0-CoA) dehydration led to the formation of (E)-2,3 eicosanoyl-CoA, which has been characterized. Our kinetic studies have determined the optimal conditions of the dehydration and also resolved the stereospecificity requirement of the dehydratase for (R)-3-OH C20:0-CoA. Isotopic dilution experiments showed that 3-hydroxy acyl-CoA dehydratase had a marked preference for (R)-3-OH C20:0-CoA. Moreover, the very-long-chain synthesis using (R)-3-OH C20:0-CoA isomer and [2-14C]malonyl-CoA was higher than that using the (S) isomer, whatever the malonyl-CoA and the 3-OH C20:0-CoA concentrations. We have also used [1-14C]3-OH C20:0-CoA to investigate the reductant requirement of the enoyl-CoA reductase of the acyl-CoA elongase complex. In the presence of NADPH, [1-14C]3-OH C20:0-CoA conversion was stimulated. Aside from the product of dehydration, i.e. (E)-2,3 eicosanoyl-CoA, we detected eicosanoyl-CoA resulting from the reduction of (E)-2,3 eicosanoyl-CoA. When we replaced NADPH with NADH, the eicosanoyl-CoA was 8- to 10-fold less abundant. Finally, in the presence of malonyl-CoA and NADPH or NADH, [1-14C]3-OH C20:0-CoA led to the synthesis of very-long-chain fatty acids. This synthesis was measured using [1-14C]3-OH C20:0-CoA and malonyl-CoA or (E)-2,3 eicosanoyl-CoA and [2-14C]malonyl-CoA. In both conditions and in the presence of NADPH, the acyl-CoA elongation activity was about 60 nmol mg−1 h−1, which is the highest ever reported for a plant system.

Cloning of human acetyl-CoA carboxylase-beta and its unique features.

Acetyl-CoA carboxylase, which has a molecular mass of 265 kDa (ACC-alpha), catalyzes the rate-limiting step in the biosynthesis of long-chain fatty acids. In this study we report the complete amino acid sequence and unique features of an isoform of ACC with a molecular mass of 275 kDa (ACC-beta), which is primarily expressed in heart and skeletal muscles. In these tissues, ACC-beta may be involved in the regulation of fatty acid oxidation, rather than fatty acid biosynthesis. ACC-beta contains an amino acid sequence at the N terminus which is about 200 amino acids long and may be uniquely related to the role of ACC-beta in controlling carnitine palmitoyltransferase I activity and fatty acid oxidation by mitochondria. If we exclude this unique sequence at the N terminus the two forms of ACC show about 75% amino acid identity. All of the known functional domains of ACC are found in the homologous regions. Human ACC-beta cDNA has an open reading frame of 7,343 bases, encoding a protein of 2,458 amino acids, with a calculated molecular mass of 276,638 Da. The mRNA size of human ACC-beta is approximately 10 kb and is primarily expressed in heart and skeletal muscle tissues, whereas ACC-alpha mRNA is detected in all tissues tested. A fragment of ACC-beta cDNA was expressed in Escherichia coli and antibodies against the peptide were generated to establish that the cDNA sequence that we cloned is that for ACC-beta.

Fluidity of the lipid domain of cell wall from Mycobacterium chelonae.

The mycobacterial cell wall contains large amounts of unusual lipids, including mycolic acids that are covalently linked to the underlying arabinogalactan-peptidoglycan complex. Hydrocarbon chains of much of these lipids have been shown to be packed in a direction perpendicular to the plane of the cell surface. In this study, we examined the dynamic properties of the organized lipid domains in the cell wall isolated from Mycobacterium chelonae grown at 30 degrees C. Differential scanning calorimetry showed that much of the lipids underwent major thermal transitions between 30 degree C and 65 degrees C, that is at temperatures above the growth temperature, a result suggesting that a significant portion of the lipids existed in a structure of extremely low fluidity in the growing cells. Spin-labeled fatty acid probes were successfully inserted into the more fluid part of the cell wall. Our model of the cell wall suggests that this domain corresponds to the outermost leaflet, a conclusion reinforced by the observation that labeling of intact cells produced electron spin resonance spectra similar to those of the isolated cell wall. Use of stearate labeled at different positions showed that the fluidity within the outer leaflet increased only slightly as the nitroxide group was placed farther away from the surface. These results are consistent with the model of mycobacterial cell wall containing an asymmetric lipid bilayer, with an internal, less fluid mycolic acid leaflet and an external, more fluid leaflet composed of lipids containing shorter chain fatty acids. The presence of the low-fluidity layer will lower the permeability of the cell wall to lipophilic antibiotics and chemotherapeutic agents and may contribute to the well-known intrinsic resistance of mycobacteria to such compounds.

PXA1, a possible Saccharomyces cerevisiae ortholog of the human adrenoleukodystrophy gene.

The adrenoleukodystrophy protein (ALDp) is an ATP-binding cassette (ABC) transporter in the human peroxisome membrane. It is defective in X chromosome-linked adrenoleukodystrophy (ALD), a neurodegenerative disorder with impaired peroxisomal oxidation of very long chain fatty acids. We report cloning and characterization of PXA1, a yeast gene encoding a protein (Pxa1p) exhibiting high similarity to ALDp. Disruption of PXA1 results in impaired growth on oleic acid and reduced ability to oxidize oleate. Pxa1p is peroxisome associated; however, in the PXA1 mutant yeast, as in ALD cells, peroxisomes are morphologically intact. Disruption of a second yeast gene, YKL741, which encodes a more distantly related ALDp homolog (Yk174p), in either wild-type or PXA1 mutant yeast, results in a growth phenotype identical to that of the PXA1 mutant. This result suggests that Yk1741p and Pxa1p may be subunits of the same transporter. Sequence analysis of Pxa1p, ALDp, and related ABC transporters reveals a possible fatty acid binding domain and a 14-amino acid EAA-like motif, previously described only in prokaryotes. Because of the similarities in sequence and function, we propose that Pxa1p is the Saccharomyces cerevisiae ortholog of ALDp.

Function and Regulation of Cytochrome P450 4V2 and the Implications in Bietti’s Crystalline Dystrophy

Thesis (Ph.D.)--University of Washington, 2016-06

Dysfonctions mitochondriales associées à l’acidose lactique du Saguenay-Lac-Saint-Jean révélées par l’étude d’un nouveau modèle murin de la maladie

Le syndrome de Leigh version canadienne-française (LSFC) est une maladie autosomale récessive causée par une mutation du gène LRPPRC, encodant une protéine du même nom. LRPPRC est impliquée dans la traduction des gènes mitochondriaux qui encodent certains complexes de la chaine respiratoire. Les répercussions biochimiques incluent un déficit tissu spécifique de la cytochrome c oxydase (COX), principalement dans le foie et le cerveau, et la survenue de crises d’acidose fatales chez 80 % des enfants atteints avant l’âge de 3-4 ans. L’identification d’options thérapeutiques demeure encore un défi de taille et ceci est en partie relié au manque de connaissances des fonctions biologiques de LRPPRC et des mécanismes impliqués dans la pathogenèse du LSFC, au niveau des dysfonctions mitochondriales résultantes. Afin d’étudier ces mécanismes, le consortium de l’acidose lactique, dont fait partie notre laboratoire, a récemment développé un modèle murin portant une ablation de LRPPRC spécifique au foie (souris H-Lrpprc-/-). L’objectif principal est de déterminer si ce modèle reproduit le phénotype pathologique observé dans les cultures de fibroblastes humains issus de biopsies de peau de patients LSFC. Dans le cadre des travaux de ce mémoire, nous avons amorcé la caractérisation de ce nouveau modèle, en examinant le phénotype général, l’histopathologie hépatique et les fonctions mitochondriales, et en nous focalisant principalement sur les fonctions respiratoires et la capacité à oxyder divers types de substrats. Nous avons observé un retard de croissance, une hépatomégalie ainsi que plusieurs anomalies histologiques du foie chez la souris HLrpprc-/-. De plus, l’ablation de LRPPRC induit un déficit du complexe IV, mais aussi de l’ATP synthase, et affecte l’oxydation des acides gras à longues chaines. À la lumière de ces résultats, nous croyons que le modèle murin H-Lrpprc-/- contribuera à l’avancement des connaissances générales sur LRPPRC, nous permettant de mieux comprendre l’influence de la protéine sur les fonctions mitochondriales.

(Table 1) Organic acid analyses from Leg 135 interstitial waters

For the first time, short-chain organic acids are described in interstitial waters from sediments and lithified materials in a backarc setting. Organic acids in interstitial waters from the Tonga forearc region were also analyzed and compared with previous organic acid analyses from the Mariana and Bonin forearc interstitial waters. In the Tonga backarc setting, propionate typically dominates the organic acid assemblage, and organic acids are a consistent feature of these interstitial waters. The persistent presence of ammonia and the dominance of propionate over formate in the backarc interstitial waters suggest that the organic acids in this setting have their origin in reductive deamination of amino acids derived from sedimentary proteinaceous material. The organic acid assemblage revealed in the samples from Hole 841B in the Tonga forearc are similar to the organic acid assemblage detected in the Mariana forearc, that is, formate dominates the assemblage over acetate or propionate. These forearc organic acid assemblages may both have formed by a similar mechanism.

(Table 1) Organic acid analyses from ODP Leg 125 interstitial waters

For the first time, short-chain organic acids are described from serpentine-associated interstitial waters. In this geologic setting, formate typically dominates the organic acid assemblage. Within the forearc setting, the organic acids are associated only with unconsolidated serpentine. Their existence may be the result of alkaline hydrolysis of ester linkages in organic matter that has been entrained in the serpentine diapir.

Supplementation of cattle fed tropical grasses with microalgae increases microbial protein production and average daily gain

A series of 3 experiments were conducted to evaluate the use of microalgae as supplements for ruminants consuming low-CP tropical grasses. In Exp. 1, the chemical composition and in vitro protein degradability of 9 algae species and 4 protein supplements were determined. In Exp. 2, rumen function and microbial protein (MCP) production were determined in Bos indicus steers fed speargrass hay alone or supplemented with Spirulina platensis, Chlorella pyrenoidosa, Dunaliella salina, or cottonseed meal (CSM). In Exp. 3, DMI and ADG were determined in B. indicus steers fed speargrass hay alone or supplemented with increasing amounts of NPN (urea combined with ammonia sulfate), CSM, or S. platensis. In Exp. 1, the CP content of S. platensis and C. pyrenoidosa (675 and 580 g/kg DM) was highest among the algae species and higher than the other protein supplements evaluated, and Schizochytrium sp. had the highest crude lipid (CL) content (198 g/kg DM). In Exp. 2, S. platensis supplementation increased speargrass hay intake, the efficiency of MCP production, the fractional outflow rate of digesta from the rumen, the concentration of NH3N, and the molar proportion of branched-chain fatty acids in the rumen fluid of steers above all other treatments. Dunaliella salina acceptance by steers was low and this resulted in no significant difference to unsupplemented steers for all parameters measured for this algae supplement. In Exp. 3, ADG linearly increased with increasing supplementary N intake from both S. platensis and NPN, with no difference between the 2 supplements. In contrast, ADG quadratically increased with increasing supplementary N intake from CSM. It was concluded that S. platensis and C. pyrenoidosa may potentially be used as protein sources for cattle grazing low-CP pastures.

Effects of early nutrition on the wnt and bone morphogenic protein pathways in the developing intestine

Infant formula is consumed by the majority of infants in the United States for at least part of the first year of life. Infant formula lacks many of the bioactive compounds that are naturally occurring in breast milk. Because of this, there has been an increased interest by the companies that manufacture infant formula to include additives that would potentially allow formula to more closely mimic breast milk activity. One such ingredient currently being added to infant formula is prebiotics. Prebiotics are non-digestible food ingredients that beneficially affect the host by selectively stimulating the growth of specific healthful bacteria in the colon. It is speculated that prebiotics replicate the activity of breast milk oligosaccharides, which through the production of butyrate by intestinal microbiota, may interact with the Wnt/BMP pathways. The Wnt/BMP pathways regulate intestinal stem cells, which determine the growth, development and maintenance of the intestine. Therefore, the objective of this study was to explore the effects that the addition of prebiotics to formula have on the regulation of the Wnt/BMP pathways when fed to neonatal piglets, a model commonly used in the study of infant nutrition. Piglets (n=5) were randomized into sow-reared (SR), fed control formula (F), or fed formula with added prebiotics (F+P). Fructooligosaccharides (FOS) (2 g/L) and polydextrose (PDX) (2 g/L) were chosen as the prebiotics for this study, because this combination had been less studied than other combinations. Ileum and ascending colon were collected at 7 and 14 days-of-age. Dry matter content, pH, and short chain fatty acid (SCFA) content was measured. The mRNA expression of β-catenin, sFRP3, sFRP4, frizzled 6, DKK1 (Wnt pathway), gremlin (BMP pathway), TNF-a, HNF-4α and osteopontin (OPN) was measured by RT-qPCR. Piglets fed the F+P diet had greater acetate concentration and lower pH in the ileum at day 14 and in the colon at day 7 and day 14 than F piglets. Butyrate concentrations were highest in SR with F+P not differing from F in ileum at day 14 and colon at day 7 and day 14. Effects of age were seen in all genes, with the exception of OPN, sFRP-3 and sFRP-4. On day 7, no effect of diet was observed in the ileum, however, mRNA expression of DKK1 and frizzled 6 were greater in F+P than SR (p≤0.05). On day 14, gremlin expression was lower and OPN was greater in the ileum of SR piglets compared to F and F+P. Also on day 14, HNF-4α mRNA expression was greater in both ileum and colon of F+P piglets and sFRP3 mRNA expression was greater in the colon than F or SR . In summary, differences were observed between gene expression of F+P and SR piglet intestines, but the supplementation of 2 g/L scFOS and 2 g/L PDX to formula did not shift expression of genes in the Wnt/BMP pathways to be more similar to SR than F. As the Wnt/BMP pathway is known to exist in a gradient along the crypt-villus axis, with Wnt expression dominating in the crypt region and BMP expression dominating in the villi, it was possible that pooling whole tissue reduced our ability to detect treatment effects that would be concentrated in either region. A method was therefore developed to remove intestinal epithelial cells along the villus-to-crypt axis. Twenty-five-day-old F and SR piglets were euthanized and ileal tissue was collected and placed in a dissociation buffer in a shaking water bath. Exfoliated cells were removed at increasing time points from 5 to 100 minutes in order to remove cells along the villus-to-crypt axis. After the final incubation, remaining mucosal tissue was removed using a sterile glass microscope slide and pooled with the final exfoliated cell isolation. After each cell collection, a section of tissue was fixed in formalin for histomorphological examination. Expression of genes in the Wnt/BMP pathways, along with crypt marker genes (CDK5 and v-myb), were measured in both whole ileal tissue, pooled epithelial cells, and separate epithelial cell isolations from the same piglet. The expression of β-catenin, HNF-4α, TNF-α, TGF-β and the crypt marker v-myb matched the expected villus-to-crypt pattern in cells collected after 10 (incubation 1), 30 (incubation 2) and 60 (incubation 3) minutes. However, expression of expression in cells collected after 100 minutes (incubation 4) was variable, which may be due to the fact that crypt cells were not efficiently removed and the presence of unwanted non-epithelial tissue. Gremlin, OPN, DKK1, sFRP3 and sFRP4 expression was not statistically different along the villus-to-crypt axis. Frizzled 6 and CDK5 did not express as we had predicted, with expression highest towards the villi. In summary, the epithelial cell collection method used was not entirely successful. While much of the gene data suggests that cells were removed along the villus-to-crypt axis through the first three incubations, the last incubation, which involved scraping the tissue, removed non-epithelial components of the mucosa, while leaving the crypts intact. In conclusion, the addition of 2 g/L PDX and 2 g/L scFOS did not cause gene expression of the Wnt/BMP pathways to mirror either F or SR expression. New isolation methods to extract cells along the crypt-villus axis should be considered, including the use of a laser capture microdissection. While this combination of prebiotics did not yield the intended effects, future research should be done on other combinations, such as the inclusion of galactooligosaccharides (GOS), which is commonly added to food products including infant formula.

Effects of feeding carnitine and ractopamine on rainbow trout (Oncorhynchus mykiss, Walbaum 1972)

L-carnitine is required for the transfer of long-chain fatty acids from the cytosol to the mitochondrial matrix for 13-oxidation of them and ractopamine, beta adrenergic agonists, have potential stimulating lipolysis and altering rates of protein degradation and synthesis. Present study was carried out to improve lipid body oxidation and protein-sparing action of fish through addition of L-carnitine and ractopamine to diet of rainbow trout, Oncorhynchus mykiss, Walbaum 1972. An eight-week feeding trial was carried out to evaluate the effects of supplementation of tree levels of L-carnitine tartrate (0, 1 and 2 g/kg) and two levels of ractopamine hydrochloride (0 and 10 ppm) on growth performance, fillet muscle fatty acid compositions and blood biochemical parameters in 288 juvenile rainbow trout (130 g) at 3X2 factorial experimental design. Ractopamine and 1 g/kg carnitine improved the specific growth rate, feed conversion ratio, protein efficiency ratio and weight gain at the end of experiment. The protein and lipid contents of fillet muscle were affected by the inclusion of 10 mg/kg ractopamine in the diet, increasing crude protein and reducing crude fat (P<0.05) of fish fillet muscle. The highest protein and lowest fat contents of fish fillet were observed in diet that contains 2 g/kg carnitine plus ractopamine. Ractopamine and carnitine increased levels of albumin, total protein and globulin in fish blood serum, but carnitine increased triacylglycerol and cholesterol. Fatty acids compositions of fish fillet were also affected by ractopamine and carnitine. All fatty acids except for eicosapentaenoic acid and docosahexaenoic acid, were increased by dietary supplementation of ractopamine. Total saturated fatty acids were not affected by carnitine. Supplementation (P>0.05). However, total n-3 poly unsaturated fatty acids were reduced by carnitine supplementation. A significant interaction was observed between ractopamine and carnitine supplementation regarding the saturated (P<0.01) and n-3 poly unsaturated fatty acid (P<0.001) of fish fillet. This study shows that supplementation of 1 g/kg carnitine and 10 ppm ractopamine could improve performance of juvenile rainbow trout and their combination in diet results in protein increment, fat reduction and change in profile of fatty acids in fillet muscle.

Dysfonctions mitochondriales associées à l’acidose lactique du Saguenay-Lac-Saint-Jean révélées par l’étude d’un nouveau modèle murin de la maladie

Le syndrome de Leigh version canadienne-française (LSFC) est une maladie autosomale récessive causée par une mutation du gène LRPPRC, encodant une protéine du même nom. LRPPRC est impliquée dans la traduction des gènes mitochondriaux qui encodent certains complexes de la chaine respiratoire. Les répercussions biochimiques incluent un déficit tissu spécifique de la cytochrome c oxydase (COX), principalement dans le foie et le cerveau, et la survenue de crises d’acidose fatales chez 80 % des enfants atteints avant l’âge de 3-4 ans. L’identification d’options thérapeutiques demeure encore un défi de taille et ceci est en partie relié au manque de connaissances des fonctions biologiques de LRPPRC et des mécanismes impliqués dans la pathogenèse du LSFC, au niveau des dysfonctions mitochondriales résultantes. Afin d’étudier ces mécanismes, le consortium de l’acidose lactique, dont fait partie notre laboratoire, a récemment développé un modèle murin portant une ablation de LRPPRC spécifique au foie (souris H-Lrpprc-/-). L’objectif principal est de déterminer si ce modèle reproduit le phénotype pathologique observé dans les cultures de fibroblastes humains issus de biopsies de peau de patients LSFC. Dans le cadre des travaux de ce mémoire, nous avons amorcé la caractérisation de ce nouveau modèle, en examinant le phénotype général, l’histopathologie hépatique et les fonctions mitochondriales, et en nous focalisant principalement sur les fonctions respiratoires et la capacité à oxyder divers types de substrats. Nous avons observé un retard de croissance, une hépatomégalie ainsi que plusieurs anomalies histologiques du foie chez la souris HLrpprc-/-. De plus, l’ablation de LRPPRC induit un déficit du complexe IV, mais aussi de l’ATP synthase, et affecte l’oxydation des acides gras à longues chaines. À la lumière de ces résultats, nous croyons que le modèle murin H-Lrpprc-/- contribuera à l’avancement des connaissances générales sur LRPPRC, nous permettant de mieux comprendre l’influence de la protéine sur les fonctions mitochondriales.