Abstract
Mitochondria play essential roles in cellular energy processes, including ATP production, control of reactive oxygen species (ROS) and apoptosis. While mitochondrial function is regulated by the dynamics of fusion and fission, mitochondrial homeostasis remains incompletely understood. Recent studies implicate dynamin-2 and dynamin-related protein-1 (Drp1, also known as DNM1L), as GTPases involved in mitochondrial fission. Here, we identify the ATPase and endocytic protein EHD1 as a novel regulator of mitochondrial fission. EHD1 depletion induces a static and elongated network of mitochondria in the cell. However, unlike dynamin-2 and Drp1, whose depletion protects cells from staurosporine-induced mitochondrial fragmentation, EHD1-depleted cells remain sensitive to staurosporine, suggesting a different mechanismfor EHD1 function. Recent studies have demonstrated that VPS35 and the retromer complex influence mitochondrial homeostasis either byMul1-mediated ubiquitylation and degradation of the fusion protein Mfn2, or by removal of inactive Drp1 from the mitochondrial membrane. We demonstrate that EHD1 and its interaction partner rabankyrin-5 interact with the retromer complex to influence mitochondrial dynamics, likely by inducing VPS35-mediated removal of inactive Drp1 from mitochondrial membranes. Our study sheds light on mitochondrial dynamics, expanding a new paradigm of endocytic protein regulation of mitochondrial homeostasis.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2359-2370 |
| Number of pages | 12 |
| Journal | Journal of cell science |
| Volume | 130 |
| Issue number | 14 |
| DOIs | |
| State | Published - Jul 15 2017 |
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Keywords
- Dynamics
- EHD1
- Endocytic recycling
- Fission
- Mitochondria
- Rabankyrin-5
- Retromer
- VPS35
ASJC Scopus subject areas
- Cell Biology
Cite this
Control of mitochondrial homeostasis by endocytic regulatory proteins. / Farmer, Trey; Reinecke, James B.; Xie, Shuwei; Bahl, Kriti; Naslavsky, Naava; Caplan, Steven H.
In: Journal of cell science, Vol. 130, No. 14, 15.07.2017, p. 2359-2370.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Control of mitochondrial homeostasis by endocytic regulatory proteins
AU - Farmer, Trey
AU - Reinecke, James B.
AU - Xie, Shuwei
AU - Bahl, Kriti
AU - Naslavsky, Naava
AU - Caplan, Steven H
PY - 2017/7/15
Y1 - 2017/7/15
N2 - Mitochondria play essential roles in cellular energy processes, including ATP production, control of reactive oxygen species (ROS) and apoptosis. While mitochondrial function is regulated by the dynamics of fusion and fission, mitochondrial homeostasis remains incompletely understood. Recent studies implicate dynamin-2 and dynamin-related protein-1 (Drp1, also known as DNM1L), as GTPases involved in mitochondrial fission. Here, we identify the ATPase and endocytic protein EHD1 as a novel regulator of mitochondrial fission. EHD1 depletion induces a static and elongated network of mitochondria in the cell. However, unlike dynamin-2 and Drp1, whose depletion protects cells from staurosporine-induced mitochondrial fragmentation, EHD1-depleted cells remain sensitive to staurosporine, suggesting a different mechanismfor EHD1 function. Recent studies have demonstrated that VPS35 and the retromer complex influence mitochondrial homeostasis either byMul1-mediated ubiquitylation and degradation of the fusion protein Mfn2, or by removal of inactive Drp1 from the mitochondrial membrane. We demonstrate that EHD1 and its interaction partner rabankyrin-5 interact with the retromer complex to influence mitochondrial dynamics, likely by inducing VPS35-mediated removal of inactive Drp1 from mitochondrial membranes. Our study sheds light on mitochondrial dynamics, expanding a new paradigm of endocytic protein regulation of mitochondrial homeostasis.
AB - Mitochondria play essential roles in cellular energy processes, including ATP production, control of reactive oxygen species (ROS) and apoptosis. While mitochondrial function is regulated by the dynamics of fusion and fission, mitochondrial homeostasis remains incompletely understood. Recent studies implicate dynamin-2 and dynamin-related protein-1 (Drp1, also known as DNM1L), as GTPases involved in mitochondrial fission. Here, we identify the ATPase and endocytic protein EHD1 as a novel regulator of mitochondrial fission. EHD1 depletion induces a static and elongated network of mitochondria in the cell. However, unlike dynamin-2 and Drp1, whose depletion protects cells from staurosporine-induced mitochondrial fragmentation, EHD1-depleted cells remain sensitive to staurosporine, suggesting a different mechanismfor EHD1 function. Recent studies have demonstrated that VPS35 and the retromer complex influence mitochondrial homeostasis either byMul1-mediated ubiquitylation and degradation of the fusion protein Mfn2, or by removal of inactive Drp1 from the mitochondrial membrane. We demonstrate that EHD1 and its interaction partner rabankyrin-5 interact with the retromer complex to influence mitochondrial dynamics, likely by inducing VPS35-mediated removal of inactive Drp1 from mitochondrial membranes. Our study sheds light on mitochondrial dynamics, expanding a new paradigm of endocytic protein regulation of mitochondrial homeostasis.
KW - Dynamics
KW - EHD1
KW - Endocytic recycling
KW - Fission
KW - Mitochondria
KW - Rabankyrin-5
KW - Retromer
KW - VPS35
UR - http://www.scopus.com/inward/record.url?scp=85024093202&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85024093202&partnerID=8YFLogxK
U2 - 10.1242/jcs.204537
DO - 10.1242/jcs.204537
M3 - Article
C2 - 28596240
AN - SCOPUS:85024093202
VL - 130
SP - 2359
EP - 2370
JO - Journal of Cell Science
JF - Journal of Cell Science
SN - 0021-9533
IS - 14
ER -