Inducible proteolytic inactivation of OPA1 mediated by the OMA1 protease in mammalian cells

A proteolytic cascade ensures that OMA1 cleaves and inactivates mitochondrial fusion protein OPA1 in times of stress, preventing damaged mitochondria from fusing with healthy organelles. (See also companion paper from Ehses et al. in this issue.

Titration of mitochondrial fusion rescues Mff-deficient cardiomyopathy

Defects in mitochondrial fusion or fission are associated with many pathologies, raising the hope that pharmacological manipulation of mitochondrial dynamics may have therapeutic benefit. This approach assumes that organ physiology can be restored by rebalancing mitochondrial dynamics, but this concept remains to be validated. We addressed this issue by analyzing mice deficient in Mff, a protein important for mitochondrial fission. Mff mutant mice die at 13 wk as a result of severe dilated cardiomyopathy leading to heart failure. Mutant tissue showed reduced mitochondrial density and respiratory chain activity along with increased mitophagy. Remarkably, concomitant deletion of the mitochondrial fusion gene Mfn1 completely rescued heart dysfunction, life span, and respiratory chain function. Our results show for the first time that retuning the balance of mitochondrial fusion and fission can restore tissue integrity and mitochondrial physiology at the whole-organ level. Examination of liver, testis, and cerebellum suggest, however, that the precise balance point of fusion and fission is cell type specific

Human MIEF1 recruits Drp1 to mitochondrial outer membranes and promotes mitochondrial fusion rather than fission

Mitochondrial morphology depends on the balance between fission and fusion events. This study identifies a receptor for the fission factor Drp1 within the mitochondrial outer membrane, which inhibits Drp1-mediated fission and activates fusion

ACBD5 and VAPB mediate membrane associations between peroxisomes and the ER

This is the final version of the article. Available from the publisher via the DOI in this record.Peroxisomes (POs) and the endoplasmic reticulum (ER) cooperate in cellular lipid metabolism and form tight structural associations, which were first observed in ultrastructural studies decades ago. PO–ER associations have been suggested to impact on a diverse number of physiological processes, including lipid metabolism, phospholipid exchange, metabolite transport, signaling, and PO biogenesis. Despite their fundamental importance to cell metabolism, the mechanisms by which regions of the ER become tethered to POs are unknown, in particular in mammalian cells. Here, we identify the PO membrane protein acyl-coenzyme A–binding domain protein 5 (ACBD5) as a binding partner for the resident ER protein vesicle-associated membrane protein-associated protein B (VAPB). We show that ACBD5–VAPB interaction regulates PO–ER associations. Moreover, we demonstrate that loss of PO–ER association perturbs PO membrane expansion and increases PO movement. Our findings reveal the first molecular mechanism for establishing PO–ER associations in mammalian cells and report a new function for ACBD5 in PO–ER tethering.This work was supported by grants from the Biotechnology and Biological Sciences Research Council (BB/K006231/1 and BB/ N01541X/1 to M. Schrader). J. Metz and M. Schrader are supported by a Wellcome Trust Institutional Strategic Support Award (WT097835MF and WT105618MA) and L.F. Godinho by a fellowship from Fundação para a Ciência e a Tecnologia, Portugal (SFRH/ BPD/90084/2012). M. Schrader and A.S. Azadi are supported by Marie Curie Initial Training Network action PerFuMe (316723). M. Islinger is supported by MEAMEDMA Anschubförderung, Medical Faculty Mannheim, University of Heidelberg

Mechanical force induces mitochondrial fission.

Eukaryotic cells are densely packed with macromolecular complexes and intertwining organelles, continually transported and reshaped. Intriguingly, organelles avoid clashing and entangling with each other in such limited space. Mitochondria form extensive networks constantly remodeled by fission and fusion. Here, we show that mitochondrial fission is triggered by mechanical forces. Mechano-stimulation of mitochondria - via encounter with motile intracellular pathogens, via external pressure applied by an atomic force microscope, or via cell migration across uneven microsurfaces - results in the recruitment of the mitochondrial fission machinery, and subsequent division. We propose that MFF, owing to affinity for narrow mitochondria, acts as a membrane-bound force sensor to recruit the fission machinery to mechanically strained sites. Thus, mitochondria adapt to the environment by sensing and responding to biomechanical cues. Our findings that mechanical triggers can be coupled to biochemical responses in membrane dynamics may explain how organelles orderly cohabit in the crowded cytoplasm

Mff is an essential factor for mitochondrial recruitment of Drp1 during mitochondrial fission in mammalian cells

Localization of the dynamin-related GTPase Drp1 to mitochondria relies on the mitochondrial fission factor Mff