MYO19

MYO19 is an actin-based myosin motor that is stably anchored to the outer mitochondrial membrane and drives actin-dependent mitochondrial motility and positioning (PMID:19932026, PMID:26659663). Membrane targeting is mediated by its C-terminal MyMOMA tail through two distinct mechanisms: direct insertion into the outer mitochondrial membrane via positively charged residues R882/K883 (whose mutation redirects the protein to the ER), and a nucleotide-state-dependent interaction with the mitochondrial GTPase Miro2 that stabilizes MYO19 at the membrane (PMID:27126804, PMID:31479585, PMID:42102968). Both anchoring modes display slow membrane dissociation kinetics, and the motor itself is a high-duty-ratio enzyme limited by slow ADP isomerization and ADP release; these kinetics, including a class-specific motor-domain tryptophan, are required for transporting mitochondria to the tips of filopodia in response to ROS and glucose-starvation signals (PMID:27126804, PMID:28912530, PMID:28912602). At ER–mitochondria contact sites, MYO19 tethers mitochondria to ER-associated actin polymerized by the formin INF2-CAAX and Spire1C—a function requiring ATPase activity and strong actin binding and controlled by metaxins—thereby promoting Drp1-mediated mitochondrial fission (PMID:36744380). During cell division MYO19 ensures symmetric mitochondrial partitioning to daughter cells; it competes with microtubule-motor adaptors for binding to Miro1/Miro2 and regulates mitochondrial levels of Drp1, dynactin, and TRAK1, with its loss causing mitotic fission failure, asymmetric partitioning, impaired respiration, elevated ROS, and cytokinesis defects (PMID:25447992, PMID:34013964). MYO19 also physically binds the myosin light chain MYL9 (PMID:39437553).

1. 2009 High

   Establishing whether a dedicated motor links mitochondria to actin, this work identified MYO19 as a myosin whose tail is necessary and sufficient for mitochondrial localization and drives actin-dependent organelle movement.

   Evidence GFP-fusion deletion analysis with live imaging and latrunculin B treatment in CAD cells

   PMID:19932026

   Open questions at the time

   • Did not define the molecular anchor on the membrane
   • Motor kinetics uncharacterized
2. 2014 High

   Addressing how mitochondria are inherited during division, depletion showed MYO19 is required for symmetric mitochondrial partitioning and cytokinesis completion, linking the motor to mitotic organelle distribution.

   Evidence siRNA knockdown with high-content live imaging and epistasis with fission/fusion modulators

   PMID:25447992

   Open questions at the time

   • Molecular receptor for MYO19 at the OMM still unknown
   • Mechanism of competition with spindle-directed transport not defined
3. 2015 High

   To localize the anchoring activity, a 30–45 residue tail motif was shown to stably attach MYO19 to the OMM and to direct mitochondria to starvation-induced filopodia tips.

   Evidence RNAi, GFP-truncation expression, and subcellular fractionation

   PMID:26659663

   Open questions at the time

   • Specific anchoring residues not yet identified
   • Whether anchoring is via lipid or protein partner unresolved
4. 2016 High

   Pinpointing the membrane-insertion determinant, alanine scanning identified R882/K883 as essential charged residues whose mutation redirects MYO19 to the ER, and kinetic assays showed slow membrane dissociation.

   Evidence Alanine-scanning mutagenesis of GFP-MyMOMA truncations with FRAP and PARF

   PMID:27126804

   Open questions at the time

   • Did not establish whether a protein receptor also contributes
   • Lipid specificity of the insertion motif not defined
5. 2017 High

   Connecting motor enzymology to function, purified-motor kinetics and mutagenesis showed MYO19's high duty ratio (slow ADP isomerization/release) and a class-specific tryptophan are required for ROS- and starvation-driven mitochondrial transport to filopodia.

   Evidence Stopped-flow transient kinetics and ATPase assays on purified Myo19-3IQ plus site-directed mutagenesis and live imaging

   PMID:28912530 PMID:28912602

   Open questions at the time

   • Number of motors needed for processive transport inferred, not directly measured
   • How ROS signaling engages the motor mechanistically unresolved
6. 2019 High

   Resolving the dual nature of OMM targeting, the MyMOMA domain was shown to use both membrane insertion and a nucleotide-state-dependent interaction with the GTPase Miro2 requiring conserved charged residues in both proteins.

   Evidence BioID, GFP-fragment recruitment assay, mutagenesis of MYO19 and Miro2, FRAP and PARF

   PMID:31479585

   Open questions at the time

   • Relative contribution of the two targeting modes in vivo not quantified
   • Role of metaxins not yet implicated
7. 2021 High

   Defining MYO19's role in mitotic mitochondrial dynamics, knockout showed it competes with microtubule-motor adaptors for Miro1/Miro2 and regulates Drp1/dynactin/TRAK1 levels, with loss causing fission failure, asymmetric partitioning, impaired respiration, and elevated ROS.

   Evidence CRISPR/Cas9 knockout in HEK293T with live imaging, Western blot, respiratory/ROS assays, and focal adhesion analysis

   PMID:34013964

   Open questions at the time

   • Direct biochemical competition with TRAK adaptors not reconstituted
   • Mechanism linking MYO19 loss to focal adhesion defects unclear
8. 2023 High

   Establishing how MYO19 promotes fission, it was shown to tether mitochondria to ER-associated actin at contact sites in an ATPase- and actin-binding-dependent manner requiring INF2-CAAX, Spire1C, and metaxins.

   Evidence ATPase-dead and working-stroke mutants, super-resolution imaging, split-luciferase ER-mitochondria contact assay, and siRNA of actin nucleators/metaxins

   PMID:36744380

   Open questions at the time

   • How metaxins control MYO19 dispersal mechanistically not detailed
   • Direct interaction between MYO19 and INF2/Spire1C not established
9. 2024 Medium

   Identifying a regulatory binding partner, MYL9 was shown to bind MYO19 directly and suppress MYO19-driven migration and EMT in NSCLC cells.

   Evidence Reciprocal Co-IP, GST pull-down, scratch wound healing, and rescue overexpression

   PMID:39437553

   Open questions at the time

   • Single lab without independent replication
   • Whether MYL9 acts as a regulatory light chain on the motor not biochemically resolved
10. 2024 Low

    Probing a possible link to cell-death regulation, knockdown placed MYO19 upstream of ferroptosis regulators ACSL4 and SLC7A11 in lung squamous carcinoma cells.

    Evidence Knockdown/overexpression with RSL3 induction, Western blot, and MDA/GSH measurement

    PMID:41568382

    Open questions at the time

    • No direct mechanistic link between MYO19 and ferroptosis machinery established
    • Single-lab knockdown/overexpression with indirect readouts
11. 2026 Medium

    Mapping context-dependent interactomes, proximity proteomics revealed MYO19 associates with distinct mitochondrial trafficking, ER-contact, and MICOS/CIOS clusters between interphase and prometaphase, with Miro2 stabilizing MYO19 in a GTPase-state-dependent manner.

    Evidence TurboID proximity biotinylation/mass spectrometry with a Miro2 T18N GTPase-dead mutant

    PMID:42102968

    Open questions at the time

    • Proximity associations not validated as direct interactions
    • Functional consequence of cell-cycle-dependent partner switching not tested

• How upstream signals (ROS, EGF/calcium) are transduced to switch MYO19 between resting and transport-competent states, and how the motor's activity is regulated by light chains and Miro nucleotide cycling in vivo, remains unresolved.
• No structural model of the autoinhibited or active motor
• Direct effect of calcium on MYO19 not demonstrated in vitro
• Light-chain regulation of duty ratio uncharacterized