Phosphoregulation on mitochondria: Integration of cell and organelle responses

Abstract

Mitochondria are highly integrated organelles that are crucial to cell adaptation and mitigating adverse physiology. Recent studies demonstrate that fundamental signal transduction pathways incorporate mitochondrial substrates into their biological programs. Reversible phosphorylation is emerging as a useful mechanism to modulate mitochondrial function in accordance with cellular changes. Critical serine/threonine protein kinases, such as the c‐Jun N‐terminal kinase (JNK), protein kinase A (PKA), PTEN‐induced kinase‐1 (PINK1), and AMP‐dependent protein kinase (AMPK), readily translocate to the outer mitochondrial membrane (OMM), the interface of mitochondria‐cell communication. OMM protein kinases phosphorylate diverse mitochondrial substrates that have discrete effects on organelle dynamics, protein import, respiratory complex activity, antioxidant capacity, and apoptosis. OMM phosphorylation events can be tempered through the actions of local protein phosphatases, such as mitogen‐activated protein kinase phosphatase‐1 (MKP‐1) and protein phosphatase 2A (PP2A), to regulate the extent and duration of signaling. The central mediators of OMM signal transduction are the scaffold proteins because the relative abundance of these accessory proteins determines the magnitude and duration of a signaling event on the mitochondrial surface, which dictates the biological outcome of a local signal transduction pathway. The concentrations of scaffold proteins, such as A‐kinase anchoring proteins (AKAPs) and Sab (or SH3 binding protein 5—SH3BP5), have been shown to influence neuronal survival and vulnerability, respectively, in models of Parkinson's disease (PD), highlighting the importance of OMM signaling to health and disease. Despite recent progress, much remains to be discovered concerning the mechanisms of OMM signaling. Nonetheless, enhancing beneficial OMM signaling events and inhibiting detrimental protein‐protein interactions on the mitochondrial surface may represent highly selective approaches to restore mitochondrial health and homeostasis and mitigate organelle dysfunction in conditions such as PD.

The Role of Reversible Protein Phosphorylation in Regulation of the Mitochondrial Electron Transport System During Hypoxia and Reoxygenation Stress in Marine Bivalves

“…Among different types of PTMs (such as phosphorylation, acetylation, succinylation, or SUMOylation), the reversible protein phosphorylation by protein kinases plays an important and not yet fully deciphered role in regulating the mitochondrial metabolism in different physiological and stress states (Stram and Payne, 2016). PTM by protein kinases provides a rapid, reversible, and energetically inexpensive mechanism to regulate the enzyme activity (Lim et al, 2016;Lucero et al, 2019). Among the mitochondrial protein kinases, serine/threonine protein kinase A (PKA) and protein kinase C (PKC) are recognized as crucial regulators of mitochondrial physiology (Lim et al, 2016).…”

“…Mitochondrial Complexes I and IV are common substrates for the PKAand PKC-mediated reversible phosphorylation during different physiological and pathological states, including exposure to H/R stress (Ogbi and Johnson, 2006;Prabu et al, 2006;Dagda and Das Banerjee, 2015;Mathers and Staples, 2019). Phosphorylation of Complex I can activate or suppress its activity depending on the species, tissue, and phosphorylation site (Lucero et al, 2019;Mathers and Staples, 2019). Complex IV is typically suppressed by phosphorylation in mammals, and this suppression plays an important role in hypoxiainduced mitochondrial dysfunction (Acin-Perez et al, 2009;Hüttemann et al, 2012;Srinivasan et al, 2013;Mahapatra et al, 2016).…”

Assessment of three essential tremor genetic loci in sporadic Parkinson's disease in Eastern China

“…Peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha (PPARGC1A), or PGC‐1a, regulates mitochondrial biogenesis and suppresses oxidative stress . Accumulation of misfolded proteins has been shown to influence neuronal survival and vulnerability in PD . It is also reported that PGC‐1a plays a protective role against 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) toxicity, which has been shown to be a causative factor of PD .…”

“…25 Accumulation of misfolded proteins has been shown to influence neuronal survival and vulnerability in PD. 26 It is also reported that PGC-1a plays a protective role against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity, which has been shown to be a causative factor of PD. 27,28 Rs17590046 in PPARGC1A was found to be significantly associated with increased risk of ET through a GWAS in an European population.…”

Mitochondria in neurodegenerative diseases

“…AKAP1/PKA protects against cerebral ischemic stroke by inhibiting Drp1‐dependent mitochondrial fission . Maribel Lucero, Ana E. Suarez, and Jeremy W. Chambers at Florida International University summarized the effects of kinases, phosphatases, and the associated adaptor proteins and scaffold proteins on the OMM in neurons . The authors reviewed the roles of specific substrate phosphorylation or dephosphorylation events including the impacts on mitochondrial dynamics, cell death, fission/fusion, and metabolism.…”