SIRT5 inhibits peroxisomal ACOX1 to prevent oxidative damage and is downregulated in liver cancer

doi:10.15252/embr.201745124

. 2018 May;19(5):e45124.

doi: 10.15252/embr.201745124. Epub 2018 Feb 28.

SIRT5 inhibits peroxisomal ACOX1 to prevent oxidative damage and is downregulated in liver cancer

Xiu-Fei Chen^{1

2

3}, Meng-Xin Tian^{4

5}, Ren-Qiang Sun^{1

2

3}, Meng-Li Zhang^{1

2

3}, Li-Sha Zhou^{1

2

3}, Lei Jin^{4

5}, Lei-Lei Chen^{1

2

3}, Wen-Jie Zhou^{1

2

3}, Kun-Long Duan^{1

2

3}, Yu-Jia Chen^{1

2

3}, Chao Gao^{1

2

3}, Zhou-Li Cheng^{1

2

3}, Fang Wang^{1

2

3}, Jin-Ye Zhang^{1

2

3}, Yi-Ping Sun^{1

2

3}, Hong-Xiu Yu^{1

2

3}, Yu-Zheng Zhao⁶, Yi Yang⁶, Wei-Ren Liu^{4

5}, Ying-Hong Shi^{4

5}, Yue Xiong^{1

2

3

7}, Kun-Liang Guan^{1

2

3

8}, Dan Ye^{9

2

3

10}

Affiliations

¹ Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Shanghai, China.
² Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
³ State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.
⁴ Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
⁵ Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China.
⁶ School of Pharmacy, East China University of Science and Technology, Shanghai, China.
⁷ Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁸ Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
⁹ Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Shanghai, China yedan@fudan.edu.cn.
¹⁰ Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.

PMID: 29491006
PMCID: PMC5934778
DOI: 10.15252/embr.201745124

SIRT5 inhibits peroxisomal ACOX1 to prevent oxidative damage and is downregulated in liver cancer

Xiu-Fei Chen et al. EMBO Rep. 2018 May.

. 2018 May;19(5):e45124.

doi: 10.15252/embr.201745124. Epub 2018 Feb 28.

Authors

Affiliations

¹ Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Shanghai, China.
² Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
³ State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.
⁴ Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
⁵ Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China.
⁶ School of Pharmacy, East China University of Science and Technology, Shanghai, China.
⁷ Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁸ Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
⁹ Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Shanghai, China yedan@fudan.edu.cn.
¹⁰ Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.

PMID: 29491006
PMCID: PMC5934778
DOI: 10.15252/embr.201745124

Abstract

Peroxisomes account for ~35% of total H₂O₂ generation in mammalian tissues. Peroxisomal ACOX1 (acyl-CoA oxidase 1) is the first and rate-limiting enzyme in fatty acid β-oxidation and a major producer of H₂O₂ ACOX1 dysfunction is linked to peroxisomal disorders and hepatocarcinogenesis. Here, we show that the deacetylase sirtuin 5 (SIRT5) is present in peroxisomes and that ACOX1 is a physiological substrate of SIRT5. Mechanistically, SIRT5-mediated desuccinylation inhibits ACOX1 activity by suppressing its active dimer formation in both cultured cells and mouse livers. Deletion of SIRT5 increases H₂O₂ production and oxidative DNA damage, which can be alleviated by ACOX1 knockdown. We show that SIRT5 downregulation is associated with increased succinylation and activity of ACOX1 and oxidative DNA damage response in hepatocellular carcinoma (HCC). Our study reveals a novel role of SIRT5 in inhibiting peroxisome-induced oxidative stress, in liver protection, and in suppressing HCC development.

Keywords: ACOX1; SIRT5; liver cancer; oxidative stress; succinylation.

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Figures

**Figure EV1. Application and identification of a genetically encoded sensor to detect H₂O₂ in the peroxisome, cytosol, and nucleus**
A
HyPer‐pero, HyPer‐cyto, and HyPer‐nuc were ectopically expressed in HeLa cells, and their subcellular localization was determined by immunofluorescence staining. Representative immunofluorescence images (original magnification, 630×; a single focal plane, scale bar, 5 μm) are shown.
B–D
HEK293 cells overexpressing the Hyper biosensor were treated with PBS, 500 μM H₂O₂, or 50 μM menadione for the indicated periods. The H₂O₂ level in the peroxisome (B), cytosol (C), and nucleus (D) was monitored as described in Materials and Methods.

**Figure 1. SIRT5 can localize in peroxisomes where it regulates H₂O₂ metabolism**
A, B
Knockdown of *SIRT5* stimulates H₂O₂ production in the peroxisome, cytosol, and nucleus. In Huh7 and HepG2 stable cells with *SIRT5* knockdown, endogenous H₂O₂ production in the indicated cellular compartments was determined by using the Hyper biosensor as described in Materials and Methods. Note: Given that the level of endogenous H₂O₂ does not change over time (within 30 min, data not shown), we have collected the excitation ratio (490/420 nm) at single time point (at 5 min). Shown are average values with standard deviation (SD) of triplicated experiments. **P < 0.01, and ***P < 0.001 for the indicated comparisons by two‐tailed unpaired Student's t‐test.
C
Wild‐type SIRT5, but not SIRT5 LQIV^del mutant, co‐localizes with peroxisomal membrane protein PMP70. Immunofluorescence staining was performed in HeLa cells overexpressing HA‐tagged wild‐type or mutant SIRT5 using the indicated antibodies as described in Materials and Methods. Representative immunofluorescence images (original magnification, 630×; a single focal plane, scale bar, 5 μm) are shown.
D
PEX7 interacts with SIRT5, but not SIRT5 LQIV^del mutant. Flag‐PEX7 was co‐expressed with HA‐tagged wild‐type or mutant SIRT5 in HEK293T cells. Proteins were purified by immunoprecipitation (IP) with Flag beads, followed by Western blot to detect SIRT5 or SIRT5 LQIV^del mutant with an HA antibody.
E
Endogenous SIRT5 co‐localizes with peroxisomal membrane protein PMP70 in cells. Immunofluorescence staining was performed in HeLa cells using the indicated antibodies as described in Materials and Methods. Representative immunofluorescence images (original magnification, 630×; a single focal plane, scale bar, 5 μm) are shown.
F
SIRT5 distributes in the peroxisomal fraction. Cellular fractionation was conducted in HepG2 cells to isolate peroxisomes and mitochondria as described in Materials and Methods. The indicated proteins were determined by Western blot analysis. #1 and #2 refer to two repeats from single fractionation.
G
SIRT5 is a matrix protein rather than a membrane protein in peroxisomes. Isolated peroxisomes from HepG2 cells were subjected to proteinase K (100 μg/ml) digestion with or without 1% Triton X‐100 pre‐treatment as indicated. Harvest the samples at indicated time points to perform Western blot assay. The indicated proteins were determined by Western blot analysis.
Source data are available online for this figure.

**Figure EV2. SIRT5 harbors a predicted PTS2 sequence and interacts with PEX7 but not PEX5**
The amino acid sequence of SIRT5 protein from the indicated species was imported into “PTSs predictor” of PEROXISOME database (*PeroxisomeDB*). As shown, SIRT5 contains a predicted PTS2 sequence (marked in red).
SIRT5 interacts with PEX7, but not PEX5. HA‐SIRT5 was co‐expressed with Flag‐PEX5 or Flag‐PEX7 in HEK293T cells. Proteins were purified by immunoprecipitation (IP) with Flag beads, followed by Western blot to detect PEX5 or PEX7 with an HA antibody.
Source data are available online for this figure.

**Figure EV3. ACOX1 is localized in the peroxisome**
ACOX1 interacts with PEX5. HA‐ACOX1 was co‐overexpressed with Flag‐PEX5 or Flag‐PEX7 in HEK293T cells. PEX proteins were purified by IP with Flag beads, followed by Western blot to detect ACOX1 with an HA antibody.
Both ACOX1 and ACOX1 SKL^del interact with SIRT5. HA‐SIRT5 was co‐overexpressed with Flag‐ACOX1 or Flag‐ACOX1 SKL^del in HEK293T cells, followed by IP with Flag beads and Western blot to detect SIRT5 with an HA antibody.
ACOX1 but not ACOX1 SKL^del mutant is localized in peroxisomes. Flag‐tagged wild‐type or mutant ACOX1 was transiently overexpressed in HeLa cells. Immunofluorescence assay was performed to detect the indicated proteins as described in Materials and Methods. Representative immunofluorescence images (original magnification, 630×; a single focal plane, scale bar, 5 μm) are shown.
ACOX1 co‐localizes with the peroxisomal marker PMP70, but not the mitochondrial marker SDHA. Flag‐ACOX1 was transiently overexpressed in HeLa cells. Immunofluorescence assay was performed to detect the indicated proteins as described in Materials and Methods. Representative immunofluorescence images (original magnification, 630×; a single focal plane, scale bar, 5 μm) are shown.
Source data are available online for this figure.

**Figure 2. SIRT5 interacts with and desuccinylates ACOX1**
Ectopically expressed ACOX1 interacts with SIRT5. Flag‐ACOX1 was overexpressed in HEK293T cells together with the individual HA‐tagged SIRT proteins as indicated. Proteins were purified by IP with Flag beads, following Western blot to detect SIRT proteins with an HA antibody.
Endogenous ACOX1 interacts with SIRT5. SIRT5 protein in Huh7 and HepG2 liver cells was purified by IP with an anti‐ACOX1 antibody, followed by Western blot to detect SIRT5 with an anti‐SIRT5 antibody.
Knockdown of *SIRT5* increases ACOX1 succinylation. In stable HEK293T cells with *SIRT5* knockdown, Flag‐ACOX1 was overexpressed. ACOX1 protein was purified by IP with Flag beads and Western blot to detect its succinylation level.
Knockout of Sirt5 increases Acox1 succinylation in mouse livers. Acox1 protein in the liver of Sirt5 KO and wild‐type littermates (n = 3 per group) was purified by IP with an anti‐ACOX1 antibody. ACOX1 succinylation was determined by anti‐succinyl‐lysine antibody.
SIRT5 dessucinylates ACOX1 *in vitro*. Flag‐ACOX1, HA‐tagged wild‐type SIRT5 and a catalytic inactive mutant SIRT5^H158Y were separately overexpressed in HEK293T cells. Proteins were purified by IP with Flag or HA beads, and then eluted with Flag or HA peptide. After incubation with wild‐type or mutant SIRT5 *in vitro*, the succinylation level of ACOX1 was determined by Western blot analysis.
Source data are available online for this figure.

**Figure 3. Lysine succinylation increases ACOX1 activity**
A
SIRT5 inactivates ACOX1 *in vitro*. Flag‐ACOX1, HA‐tagged wild‐type SIRT5, and a catalytic inactive mutant SIRT5^H158Y were separately overexpressed in HEK293T cells. Proteins were purified by IP with Flag or HA beads, and then eluted with Flag or HA peptide. After incubation with wild‐type or mutant SIRT5 *in vitro*, the enzyme activity of ACOX1 was determined as described in Materials and Methods.
B
ACOX1 activity is increased by lysine succinylation. Purified Flag‐ACOX1 was incubated with or without succinyl‐CoA (0.1 mM) at 37°C for 30 min, followed by measurement of the enzyme activity of ACOX1 as described in Materials and Methods.
C
Knockdown of *SIRT5* increases ACOX1 activity. In stable HEK293T cells with *SIRT5* knockdown, Flag‐ACOX1 was ectopically expressed. ACOX1 protein was purified by IP with Flag beads and then eluted with Flag peptide, followed by measurement of its succinylation level and enzyme activity as described in Materials and Methods. The correlation between ACOX1 succinylation level and its enzyme activity is shown.
D
Knockout of Sirt5 increases Acox1 activity in mouse livers. Acox1 protein in the liver of Sirt5 KO and wild‐type littermates (n = 3 per group) was purified by IP with an anti‐ACOX1 antibody. Acox1 enzyme activity was measured as described in Materials and Methods.
E, F
*SDHA* knockdown leads to increased succinylation and activity of ACOX1. In HepG2 cells with stable *SDHA* knockdown, ACOX1 protein was purified by IP with an anti‐ACOX1 antibody, followed by measurement of its succinylation level (E) and enzyme activity (F) as described in Materials and Methods.
Data information: Shown are average values with standard deviation (SD) of triplicated experiments. *P < 0.05, and **P < 0.01 for the indicated comparisons by two‐tailed unpaired Student's t‐test. n.s. = not significant.Source data are available online for this figure.

**Figure 4. SIRT5‐regulated succinylation activates ACOX1 through promoting its dimer formation**
SIRT5 impairs subunit interaction of ACOX1 protein. HA‐tagged wild‐type SIRT5 and a catalytic inactive mutant SIRT5^H158Y were each expressed in HEK293T cells co‐expressing HA‐ACOX1 and Flag‐ACOX1. Flag‐ACOX1 was purified by IP with Flag beads, and then, Western blot was performed to detect the interaction with HA‐ACOX1 by an HA antibody.
SIRT5 inhibits the formation of dimeric ACOX1. HA‐tagged wild‐type SIRT5 and a catalytic inactive mutant SIRT5^H158Y were each expressed in HEK293T cells co‐expressing Flag‐ACOX1, followed by treatments with or without 2.3% (v/v) glutaraldehyde. The formation of ACOX1 monomer and dimer was determined by Western blotting.
*SIRT5* knockdown enhances the interaction of ACOX1 protein subunits. HA‐ACOX1 and Flag‐ACOX1 were transiently co‐expressed in HEK293T cells with stable *SIRT5* knockdown. Flag‐ACOX1 was purified by IP with Flag beads, followed by Western blot to detect its interaction with HA‐ACOX1 with an HA antibody.
*SIRT5* knockdown promotes the formation of dimeric ACOX1. Flag‐ACOX1 was expressed in HEK293T cells with stable *SIRT5* knockdown. The transfected cell lysates were treated with 2.3% (v/v) glutaraldehyde. The formation of ACOX1 monomer and dimer was determined by Western blotting.
Knockout of *Sirt5* promotes the formation of dimeric Acox1 in mouse livers. Acox1 protein in the liver of Sirt5 KO and wild‐type littermate was purified by IP with an anti‐ACOX1 antibody, followed by treatment with 2.3% (v/v) glutaraldehyde. The formation of Acox1 monomer and dimer was determined by Western blotting.
Source data are available online for this figure.

**Figure 5. SIRT5‐regulated lysine succinylation stimulates ACOX1 to promote anchorage‐independent growth in HepG2 liver cells**
A
*ACOX1* knockdown diminishes the effect of *SIRT5* knockdown on increasing H₂O₂ production. In HepG2 stable cells with single or double knockdown of *SIRT5*/*ACOX1*, H₂O₂ production in the indicated cellular compartments was determined by using the Hyper biosensor as described in Materials and Methods.
B
*ACOX1* knockdown impairs the effect of *SIRT5* knockdown on increasing ROS. In HepG2 stable cells with single or double knockdown of *SIRT5*/*ACOX1*, ROS level was determined in cell extracts as described in Materials and Methods.
C
*ACOX1* knockdown impairs the effect of *SIRT5* knockdown on inducing oxidative DNA damage response. In HepG2 stable cells with single or double knockdown of *SIRT5*/*ACOX1*, the indicated classical oxidative DNA damage response markers were determined by Western blot analysis, completed in biological triplicate.
D, E
*ACOX1* knockdown impairs the effect of *SIRT5* knockdown on promoting anchorage‐independent growth in HepG2 liver cells. The capability of HepG2 cells with single or double knockdown of *SIRT5*/*ACOX1* to exhibit anchorage‐independent growth was determined by performing soft‐agar colony formation assay as described in Materials and Methods. Representative images for soft‐agar colony formation (D) and the related quantified result (E) are shown. The other images are presented in Appendix Fig S11.
Data information: Shown are average values with standard deviation (SD) of triplicated experiments. *P < 0.05, **P < 0.01, and ***P < 0.001 for the indicated comparisons by two‐tailed unpaired Student's t‐test.Source data are available online for this figure.

**Figure EV4. *SDHA* knockdown leads to increased H₂O₂ and ROS, and induced oxidative DNA damage response**
Knockdown of *SDHA* stimulates H₂O₂ production in the peroxisome, cytosol, and nucleus. In HepG2 cells with stable *SDHA* knockdown, endogenous H₂O₂ production in the indicated cellular compartments was determined by using the Hyper biosensor as described in Materials and Methods. Note: Given that the level of endogenous H₂O₂ does not change over time, we have collected the excitation ratio (490/420 nm) at single time point (at 5 min).
Knockdown of *SDHA* increases cellular ROS. In HepG2 cells with stable *SDHA* knockdown, ROS level was determined in cell extracts as described in Materials and Methods.
Knockdown of *SDHA* induces oxidative DNA damage response. In HepG2 cells with stable *SDHA* knockdown, the indicated classical oxidative DNA damage response markers were determined by Western blot analysis.
Data information: Shown are average values with standard deviation (SD) of triplicated experiments. **P < 0.01, and ***P < 0.001 for the indicated comparisons by two‐tailed unpaired Student's t‐test. n.s. = not significant.Source data are available online for this figure.

**Figure EV5. *ACOX1* knockdown partially blocks the effect of *SDHA* knockdown on increasing cellular H₂O₂ and ROS in HepG2 cells**
*ACOX1* knockdown partially diminishes the effect of *SDHA* knockdown on increasing H₂O₂. In HepG2 stable cells with single or double knockdown of *SDHA*/*ACOX1*, endogenous H₂O₂ level in the indicated cellular compartments was determined by using the Hyper biosensor as described in Materials and Methods. Note: given that the level of endogenous H₂O₂ does not change over time, we have collected the excitation ratio (490/420 nm) at single time point (at 5 min).
*ACOX1* knockdown partially impairs the effect of *SDHA* knockdown on increasing ROS. In HepG2 stable cells with single or double knockdown of *SDHA*/*ACOX1*, ROS level was determined in cell extracts as described in Materials and Methods.
Data information: Shown are average values with standard deviation (SD) of triplicated experiments. *P < 0.05, **P < 0.01, and ***P < 0.001 for the indicated comparisons by two‐tailed unpaired Student's t‐test. n.s. = not significant.

**Figure 6. Increased ACOX1 succinylation and activity are associated with reduced SIRT5 expression in HCC tumors**
A
HCC tumors show reduced SIRT5 expression and increased ACOX1 succinylation. In total, 10 pairs of HCC tumor tissues (T) and peritumoral tissues (P) paired samples, ACOX1 protein was immunopurified with an anti‐ACOX1 antibody, followed by Western blot to detect its succinylation. Protein levels of ACOX1 and SIRT5 were determined by direct Western blot. Relative ACOX1 and SIRT5 protein levels were normalized against β‐actin protein.
B
ACOX1 activity is increased in HCC tumors. Purified ACOX1 protein in 10 pairs of HCC tumors and peritumoral tissues in (A) was subjected to its enzyme activity assay as described in Materials and Methods. The graph boxes delimit the first and third quartiles. The horizontal lines represent the data medians. Whiskers delimit the lowest and the highest value within 1.5 of the interquartile range (IQR) of the lower and the upper quartiles, respectively.
C, D
SIRT5 protein expression is downregulated in HCC tumors. In a study cohort consisting of 78 HCC patients, the SIRT5 protein was detected by IHC staining as described in Materials and Methods (D). Representative IHC images (original magnification, 200×; a single focal plane, scale bar, 50 μm) are shown.
E
γH2AX levels show a negative correlation with SIRT5 protein levels in HCC tumors. In a cohort consisting of 118 HCC patients (each has two repeats), the γH2AX and SIRT5 protein levels in the same samples were detected by IHC staining as described in Materials and Methods, followed by quantitative assessment.
F, G
High SIRT5 expression is associated with favorable prognosis in HCC patients. In a tissue microarray composed of primary tumors from 316 consecutive curative HCC patients, the SIRT5 protein was detected by IHC staining as described in Materials and Methods. The correlation between SIRT5 staining intensity and OS (overall survival) or TTR (time to recurrence) was assessed by Kaplan–Meier method and log‐rank test, respectively.
H
A proposed model illustrating SIRT5‐dependent lysine succinylation in regulating ACOX1 activity. As shown, lysine succinylation is increased by either SIRT5 loss or SDH dysfunction. Lysine succinylation can activate ACOX1 by promoting the formation of dimeric ACOX1, thereby stimulating H₂O₂ production in peroxisomes.
Data information: *P < 0.05, **P < 0.01, and ***P < 0.001 for the indicated comparisons by two‐tailed unpaired Student's t‐test in (B, C) or log‐rank test in (F, G).Source data are available online for this figure.

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References

1. Poirier Y, Antonenkov VD, Glumoff T, Hiltunen JK (2006) Peroxisomal beta‐oxidation–a metabolic pathway with multiple functions. Biochem Biophys Acta 1763: 1413–1426 - PubMed
1. Wanders RJ, Ferdinandusse S, Brites P, Kemp S (2010) Peroxisomes, lipid metabolism and lipotoxicity. Biochem Biophys Acta 1801: 272–280 - PubMed
1. Shimozawa N (2011) Molecular and clinical findings and diagnostic flowchart of peroxisomal diseases. Brain Develop 33: 770–776 - PubMed
1. Lazarow PB (2003) Peroxisome biogenesis: advances and conundrums. Curr Opin Cell Biol 15: 489–497 - PubMed
1. Delille HK, Bonekamp NA, Schrader M (2006) Peroxisomes and disease ‐ an overview. Int J Biomed Sci 2: 308–314 - PMC - PubMed

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[1] Poirier Y, Antonenkov VD, Glumoff T, Hiltunen JK (2006) Peroxisomal beta‐oxidation–a metabolic pathway with multiple functions. Biochem Biophys Acta 1763: 1413–1426 - PubMed

[2] Poirier Y, Antonenkov VD, Glumoff T, Hiltunen JK (2006) Peroxisomal beta‐oxidation–a metabolic pathway with multiple functions. Biochem Biophys Acta 1763: 1413–1426 - PubMed

[3] Wanders RJ, Ferdinandusse S, Brites P, Kemp S (2010) Peroxisomes, lipid metabolism and lipotoxicity. Biochem Biophys Acta 1801: 272–280 - PubMed

[4] Wanders RJ, Ferdinandusse S, Brites P, Kemp S (2010) Peroxisomes, lipid metabolism and lipotoxicity. Biochem Biophys Acta 1801: 272–280 - PubMed

[5] Shimozawa N (2011) Molecular and clinical findings and diagnostic flowchart of peroxisomal diseases. Brain Develop 33: 770–776 - PubMed

[6] Shimozawa N (2011) Molecular and clinical findings and diagnostic flowchart of peroxisomal diseases. Brain Develop 33: 770–776 - PubMed

[7] Lazarow PB (2003) Peroxisome biogenesis: advances and conundrums. Curr Opin Cell Biol 15: 489–497 - PubMed

[8] Lazarow PB (2003) Peroxisome biogenesis: advances and conundrums. Curr Opin Cell Biol 15: 489–497 - PubMed

[9] Delille HK, Bonekamp NA, Schrader M (2006) Peroxisomes and disease ‐ an overview. Int J Biomed Sci 2: 308–314 - PMC - PubMed

[10] Delille HK, Bonekamp NA, Schrader M (2006) Peroxisomes and disease ‐ an overview. Int J Biomed Sci 2: 308–314 - PMC - PubMed

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SIRT5 inhibits peroxisomal ACOX1 to prevent oxidative damage and is downregulated in liver cancer

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SIRT5 inhibits peroxisomal ACOX1 to prevent oxidative damage and is downregulated in liver cancer

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