Control of mitochondrial homeostasis by endocytic regulatory proteins

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 mechanism for EHD1 function. Recent studies have demonstrated that VPS35 and the retromer complex influence mitochondrial homeostasis either by Mul1-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.

Tying trafficking to fusion and fission at the mighty mitochondria

“…For example, several VPS26A mutations have been implicated in atypical PD . Moreover, a recent study has demonstrated that extended/accessory members of the retromer complex, including the Eps15 homology domain protein 1 (EHD1), and its interaction partner, Rabankyrin‐5, also influence mitochondrial homeostasis . EHD1, an ATPase with homology to the dynamin family of GTPases, has a well‐established role in regulating recycling from the endocytic recycling compartment to the plasma membrane, and probably functions in the fission of tubules and vesicles from endosomes .…”

“…As predicted, both EHD1 and Rabankyrin‐5 affect mitochondrial homeostasis and dynamics . Upon either EHD1‐ or Rabankyrin‐5‐depletion, mitochondria become highly static and elongated in nature, reminiscent of Drp1‐depletion.…”

“…Upon either EHD1‐ or Rabankyrin‐5‐depletion, mitochondria become highly static and elongated in nature, reminiscent of Drp1‐depletion. Although an interaction was observed between EHD1 and MUL1, the ubiquitin ligase responsible for regulating Mfn2, the latter's expression levels failed to increase as anticipated if less proteasomal degradation of Mfn2 was occurring upon EHD1‐depletion . Accordingly, EHD1 and Rabankyrin‐5 most probably regulate VPS35 expression and/or its subcellular distribution, potentially controlling the level of active Drp1 at mitochondrial constriction sites.…”

Mitochondrial dynamics, mitophagy and biogenesis in neonatal hypoxic‐ischaemic brain injury

“…The processes of fission and fusion are regulated by members of the GTPase Dynamin family. Fission is triggered through Drp1 and fusion through Mfn1/2 (outer mitochondrial membrane fusion) and OPA1 (inner mitochondrial membrane fusion) . Both fission and fusion proteins are regulated through proteolysis and post‐translational modifications .…”

“…Drp1 originates from nuclear DNA and following translation, remains cytosolic , undergoing post‐translational modification, including phosphorylation prior to recruitment to the mitochondria . Although contact with the endoplasmic reticulum is believed to designate the fission point on the mitochondrion , Drp1 is essential for the fission process, inducing fission via its GTPase activity following self‐assembly .…”