Post-transcriptional regulation of mitochondrial function

RNA-binding proteins (RBPs) can control each step of the mRNA life cycle, such as splicing, nuclear export, stability, degradation, localization, and translation efficiency. Thus, RBPs can modulate the final amount of protein level and play an important role in fine-tuning many cellular processes. Surprisingly, the role of specific RBPs to allow the dynamic and coordinated expression of functionally related mitochondrial proteins has begun to emerge only recently. These RBPs define specific post-transcriptional RNA regulons that fine-tune mitochondrial gene expression, thus tailoring the effects of broad transcriptional responses to specific demands or affecting mitochondrial biogenesis independently from de novo transcription. Moreover, a handful of RBPs promote translation of mitochondrial proteins in close proximity to the organelle. Here, we review the molecular components that play a role in these elaborate and flexible mechanisms, and discuss the physiological implications of post-transcriptional regulation for mitochondrial function

A concert of RNA-binding proteins coordinates mitochondrial function

Mitochondria are dynamic and plastic organelles, which flexibly adapt morphology, ATP production, and metabolic function to meet extrinsic challenges and demands. Regulation of mitochondrial biogenesis is essential during development and in adult life to survive stress and pathological insults, and is achieved not only by increasing mitochondrial mass, but also by remodeling the organellar proteome, metabolome, and lipidome. In the last decade, the post-transcriptional regulation of the expression of nuclear-encoded mitochondrial proteins has emerged as a fast, flexible, and powerful mechanism to shape mitochondrial function and coordinate it with other cellular processes. At the heart of post-transcriptional responses are a number of RNA-binding proteins that specifically bind mRNAs encoding mitochondrial proteins and define their fate, by influencing transcript maturation, stability, translation, and localization. Thus, RNA-binding proteins provide a uniquely complex regulatory code that orchestrates mitochondrial function during physiological and pathological conditions

CLUH granules coordinate translation of mitochondrial proteins with mTORC1 signaling and mitophagy

Mitochondria house anabolic and catabolic processes that must be balanced and adjusted to meet cellular demands. The RNA-binding protein CLUH (clustered mitochondria homolog) binds mRNAs of nuclear-encoded mitochondrial proteins and is highly expressed in the liver, where it regulates metabolic plasticity. Here, we show that in primary hepatocytes, CLUH coalesces in specific ribonucleoprotein particles that define the translational fate of target mRNAs, such as Pcx, Hadha, and Hmgcs2, to match nutrient availability. Moreover, CLUH granules play signaling roles, by recruiting mTOR kinase and the RNA-binding proteins G3BP1 and G3BP2. Upon starvation, CLUH regulates translation of Hmgcs2, involved in ketogenesis, inhibits mTORC1 activation and mitochondrial anabolic pathways, and promotes mitochondrial turnover, thus allowing efficient reprograming of metabolic function. In the absence of CLUH, a mitophagy block causes mitochondrial clustering that is rescued by rapamycin treatment or depletion of G3BP1 and G3BP2. Our data demonstrate that metabolic adaptation of liver mitochondria to nutrient availability depends on a compartmentalized CLUH-dependent post-transcriptional mechanism that controls both mTORC1 and G3BP signaling and ensures survival

Astrocyte-specific deletion of the mitochondrial m-AAA protease reveals glial contribution to neurodegeneration

Mitochondrial dysfunction causes neurodegeneration but whether impairment of mitochondrial homeostasis in astrocytes contributes to this pathological process remains largely unknown. The m-AAA protease exerts quality control and regulatory functions crucial for mitochondrial homeostasis. AFG3L2, which encodes one of the subunits of the m-AAA protease, is mutated in spinocerebellar ataxia SCA28 and in infantile syndromes characterized by spastic-ataxia, epilepsy and premature death. Here, we investigate the role of Afg3l2 and its redundant homologue Afg3l1 in the Bergmann glia (BG), radial astrocytes of the cerebellum that have functional connections with Purkinje cells (PC) and regulate glutamate homeostasis. We show that astrocyte-specific deletion of Afg3l2 in the mouse leads to late-onset motor impairment and to degeneration of BG, which display aberrant morphology, altered expression of the glutamate transporter EAAT2, and a reactive inflammatory signature. The neurological and glial phenotypes are drastically exacerbated when astrocytes lack both Afg31l and Afg3l2, and therefore, are totally depleted of the m-AAA protease. Moreover, mitochondrial stress responses and necroptotic markers are induced in the cerebellum. In both mouse models, targeted BG show a fragmented mitochondrial network and loss of mitochondrial cristae, but no signs of respiratory dysfunction. Importantly, astrocyte-specific deficiency of Afg3l1 and Afg3l2 triggers secondary morphological degeneration and electrophysiological changes in PCs, thus demonstrating a non-cell-autonomous role of glia in neurodegeneration. We propose that astrocyte dysfunction amplifies both neuroinflammation and glutamate excitotoxicity in patients carrying mutations in AFG3L2, leading to a vicious circle that contributes to neuronal death