Testicular ACE regulates sperm metabolism and fertilization through the transcription factor PPARγ
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved..
Testis angiotensin-converting enzyme (tACE) plays a critical role in male fertility, but the mechanism is unknown. By using ACE C-domain KO (CKO) mice which lack tACE activity, we found that ATP in CKO sperm was 9.4-fold lower than WT sperm. Similarly, an ACE inhibitor (ACEi) reduced ATP production in mouse sperm by 72%. Metabolic profiling showed that tACE inactivation severely affects oxidative metabolism with decreases in several Krebs cycle intermediates including citric acid, cis-aconitic acid, NAD, α-ketoglutaric acid, succinate, and L-malic acid. We found that sperms lacking tACE activity displayed lower levels of oxidative enzymes (CISY, ODO1, MDHM, QCR2, SDHA, FUMH, CPT2, and ATPA) leading to a decreased mitochondrial respiration rate. The reduced energy production in CKO sperms leads to defects in their physiological functions including motility, acrosine activity, and fertilization in vitro and in vivo. Male mice treated with ACEi show severe impairment in reproductive capacity when mated with female mice. In contrast, an angiotensin II receptor blocker (ARB) had no effect. CKO sperms express significantly less peroxisome proliferators-activated receptor gamma (PPARγ) transcription factor, and its blockade eliminates the functional differences between CKO and WT sperms, indicating PPARγ might mediate the effects of tACE on sperm metabolism. Finally, in a cohort of human volunteers, in vitro treatment with the ramipril or a PPARγ inhibitor reduced ATP production in human sperm and hence its motility and acrosine activity. These findings may have clinical significance since millions of people take ACEi daily, including men who are reproductively active.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:300 |
|---|---|
| Enthalten in: |
The Journal of biological chemistry - 300(2024), 1 vom: 04. Jan., Seite 105486 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Shibata, Tomohiro [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 07.02.2024 Date Revised 07.02.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.jbc.2023.105486 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM364840773 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM364840773 | ||
| 003 | DE-627 | ||
| 005 | 20240207232123.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.jbc.2023.105486 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1283.xml |
| 035 | |a (DE-627)NLM364840773 | ||
| 035 | |a (NLM)37992807 | ||
| 035 | |a (PII)S0021-9258(23)02514-0 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Shibata, Tomohiro |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Testicular ACE regulates sperm metabolism and fertilization through the transcription factor PPARγ |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 07.02.2024 | ||
| 500 | |a Date Revised 07.02.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a Testis angiotensin-converting enzyme (tACE) plays a critical role in male fertility, but the mechanism is unknown. By using ACE C-domain KO (CKO) mice which lack tACE activity, we found that ATP in CKO sperm was 9.4-fold lower than WT sperm. Similarly, an ACE inhibitor (ACEi) reduced ATP production in mouse sperm by 72%. Metabolic profiling showed that tACE inactivation severely affects oxidative metabolism with decreases in several Krebs cycle intermediates including citric acid, cis-aconitic acid, NAD, α-ketoglutaric acid, succinate, and L-malic acid. We found that sperms lacking tACE activity displayed lower levels of oxidative enzymes (CISY, ODO1, MDHM, QCR2, SDHA, FUMH, CPT2, and ATPA) leading to a decreased mitochondrial respiration rate. The reduced energy production in CKO sperms leads to defects in their physiological functions including motility, acrosine activity, and fertilization in vitro and in vivo. Male mice treated with ACEi show severe impairment in reproductive capacity when mated with female mice. In contrast, an angiotensin II receptor blocker (ARB) had no effect. CKO sperms express significantly less peroxisome proliferators-activated receptor gamma (PPARγ) transcription factor, and its blockade eliminates the functional differences between CKO and WT sperms, indicating PPARγ might mediate the effects of tACE on sperm metabolism. Finally, in a cohort of human volunteers, in vitro treatment with the ramipril or a PPARγ inhibitor reduced ATP production in human sperm and hence its motility and acrosine activity. These findings may have clinical significance since millions of people take ACEi daily, including men who are reproductively active | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a ATP | |
| 650 | 4 | |a PPARγ | |
| 650 | 4 | |a fertilization | |
| 650 | 4 | |a male fertility | |
| 650 | 4 | |a metabolism | |
| 650 | 4 | |a sperm | |
| 650 | 4 | |a testicular ACE (tACE) | |
| 650 | 7 | |a Adenosine Triphosphate |2 NLM | |
| 650 | 7 | |a 8L70Q75FXE |2 NLM | |
| 650 | 7 | |a Angiotensin-Converting Enzyme Inhibitors |2 NLM | |
| 650 | 7 | |a PPAR gamma |2 NLM | |
| 650 | 7 | |a Peptidyl-Dipeptidase A |2 NLM | |
| 650 | 7 | |a EC 3.4.15.1 |2 NLM | |
| 650 | 7 | |a Mitochondrial Proteins |2 NLM | |
| 700 | 1 | |a Bhat, Shabir A |e verfasserin |4 aut | |
| 700 | 1 | |a Cao, DuoYao |e verfasserin |4 aut | |
| 700 | 1 | |a Saito, Suguru |e verfasserin |4 aut | |
| 700 | 1 | |a Bernstein, Ellen A |e verfasserin |4 aut | |
| 700 | 1 | |a Nishi, Erika |e verfasserin |4 aut | |
| 700 | 1 | |a Medenilla, Juliet D |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Erica T |e verfasserin |4 aut | |
| 700 | 1 | |a Chan, Jessica L |e verfasserin |4 aut | |
| 700 | 1 | |a Pisarska, Margareta D |e verfasserin |4 aut | |
| 700 | 1 | |a Tourtellotte, Warren G |e verfasserin |4 aut | |
| 700 | 1 | |a Giani, Jorge F |e verfasserin |4 aut | |
| 700 | 1 | |a Bernstein, Kenneth E |e verfasserin |4 aut | |
| 700 | 1 | |a Khan, Zakir |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t The Journal of biological chemistry |d 1945 |g 300(2024), 1 vom: 04. Jan., Seite 105486 |w (DE-627)NLM000004995 |x 1083-351X |7 nnns |
| 773 | 1 | 8 | |g volume:300 |g year:2024 |g number:1 |g day:04 |g month:01 |g pages:105486 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.jbc.2023.105486 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 300 |j 2024 |e 1 |b 04 |c 01 |h 105486 | ||