bims-midbra 2022-02-27 papers

Issue of 2022‒02‒27
three papers selected by
Ana Paula Mendonça
University of Padova

Biochem J. 2022 Feb 17. 479(4): 525-536

FoxO transcription factors in mitochondrial homeostasis.

Mitochondria play essential roles in cellular energetics, biosynthesis, and signaling transduction. Dysfunctional mitochondria have been implicated in different diseases such as obesity, diabetes, cardiovascular disease, nonalcoholic fatty liver disease, neurodegenerative disease, and cancer. Mitochondrial homeostasis is controlled by a triad of mitochondrial biogenesis, dynamics (fusion and fission), and autophagy (mitophagy). Studies have underscored FoxO transcription factors as key mitochondrial regulators. Specifically, FoxOs regulate mitochondrial biogenesis by dampening NRF1-Tfam and c-Myc-Tfam cascades directly, and inhibiting NAD-Sirt1-Pgc1α cascade indirectly by inducing Hmox1 or repressing Fxn and Urod. In addition, FoxOs mediate mitochondrial fusion (via Mfn1 and Mfn2) and fission (via Drp1, Fis1, and MIEF2), during which FoxOs elicit regulatory mechanisms at transcriptional, posttranscriptional (e.g. via miR-484/Fis1), and posttranslational (e.g. via Bnip3-calcineurin mediated Drp1 dephosphorylation) levels. Furthermore, FoxOs control mitochondrial autophagy in the stages of autophagosome formation and maturation (e.g. initiation, nucleation, and elongation), mitochondria connected to and engulfed by autophagosome (e.g. via PINK1 and Bnip3 pathways), and autophagosome-lysosome fusion to form autolysosome for cargo degradation (e.g. via Tfeb and cathepsin proteins). This article provides an up-to-date view of FoxOs regulating mitochondrial homeostasis and discusses the potential of targeting FoxOs for therapeutics.

Keywords: FoxO; autophagy; fusion and fission; homeostasis; mitochondrial biogenesis; mitophagy

DOI: https://doi.org/10.1042/BCJ20210777

Neuron. 2022 Feb 19. pii: S0896-6273(22)00105-2. [Epub ahead of print]

Neuronal mitochondria transport Pink1 mRNA via synaptojanin 2 to support local mitophagy.

Angelika B Harbauer, J Tabitha Hees, Simone Wanderoy, Inmaculada Segura, Whitney Gibbs, Yiming Cheng, Martha Ordonez, Zerong Cai, Romain Cartoni, Ghazaleh Ashrafi, Chen Wang, Fabiana Perocchi, Zhigang He, Thomas L Schwarz.

PTEN-induced kinase 1 (PINK1) is a short-lived protein required for the removal of damaged mitochondria through Parkin translocation and mitophagy. Because the short half-life of PINK1 limits its ability to be trafficked into neurites, local translation is required for this mitophagy pathway to be active far from the soma. The Pink1 transcript is associated and cotransported with neuronal mitochondria. In concert with translation, the mitochondrial outer membrane proteins synaptojanin 2 binding protein (SYNJ2BP) and synaptojanin 2 (SYNJ2) are required for tethering Pink1 mRNA to mitochondria via an RNA-binding domain in SYNJ2. This neuron-specific adaptation for the local translation of PINK1 provides distal mitochondria with a continuous supply of PINK1 for the activation of mitophagy.

Keywords: OMP25; PINK1; Parkinson disease; RNA transport; SYNJ2BP; hitchhiking; local translation; mitophagy; synaptojanin2

DOI: https://doi.org/10.1016/j.neuron.2022.01.035

J Membr Biol. 2022 Feb 26.

Metal-Binding Propensity in the Mitochondrial Dynamin-Related Protein 1.

Krishnendu Roy, Thomas J Pucadyil.

Dynamin-related protein1 (Drp1) functions to divide mitochondria and peroxisomes by binding specific adaptor proteins and lipids, both of which are integral to the limiting organellar membrane. In efforts to understand how such multivalent interactions regulate Drp1 functions, in vitro reconstitution schemes rely on recruiting soluble portions of the adaptors appended with genetically encoded polyhistidine tags onto membranes containing Ni2+-bound chelator lipids. These strategies are facile and circumvent the challenge in working with membrane proteins but assume that binding is specific to proteins carrying the polyhistidine tag. Here, we find using chelator lipids and chelator beads that both native and recombinant Drp1 directly bind Ni2+ ions. Metal binding, therefore, represents a potential strategy to deplete or purify Drp1 from native tissue lysates. Importantly, high concentrations of the metal in solution inhibit GTP hydrolysis and renders Drp1 inactive in membrane fission. Together, our results emphasize a metal-binding propensity, which could significantly impact Drp1 functions.

Keywords: Drp1; GTPase activity; Membrane fission; Protein-lipid interactions; Transition metal binding

DOI: https://doi.org/10.1007/s00232-022-00221-5