Mitochondrial Respiration Controls Lysosomal Function during Inflammatory T Cell Responses

Abstract

The endolysosomal system is critical for the maintenance of cellular homeostasis. However, how endolysosomal compartment is regulated by mitochondrial function is largely unknown. We have generated a mouse model with defective mitochondrial function in CD4(+) T lymphocytes by genetic deletion of the mitochondrial transcription factor A (Tfam). Mitochondrial respiration deficiency impairs lysosome function, promotes p62 and sphingomyelin accumulation, and disrupts endolysosomal trafficking pathways and autophagy, thus linking a primary mitochondrial dysfunction to a lysosomal storage disorder. The impaired lysosome function in Tfam-deficient cells subverts T cell differentiation toward proinflammatory subsets and exacerbates the in vivo inflammatory response. Restoration of NAD(+) levels improves lysosome function and corrects the inflammatory defects in Tfam-deficient T cells. Our results uncover a mechanism by which mitochondria regulate lysosome function to preserve T cell differentiation and effector functions, and identify strategies for intervention in mitochondrial-related diseases.

Acute and chronic mitochondrial respiratory chain deficiency differentially regulate lysosomal biogenesis

“…Therefore, the effect is valid in post-mitotic tissues as well as primary cells in culture. Our model of lysosomal biogenesis activation by acute mitochondrial stress is in agreement with other models of acute mitochondrial stress, such as mitophagy bursts and T-cell activation, which also induce TFEB and lysosomal biogenesis141516. The exact kinetics of the biphasic effect may vary depending on the cell type employed, the treatment (compound, concentration) and the genetic environment.…”

“…Recently, three studies addressed the effect of mitochondrial malfunction and of mitophagy on lysosomal function and biogenesis. In cultured cells, short-term mitophagy bursts affect the regulation of the microphtalmia transcription factor family1516, which includes TFEB, MITF, TFEC and TFE3, while mtDNA depletion, and consequent loss of respiratory chain function, perturbs lysosomal function and triggers a program of incomplete lysosomal biogenesis in mouse T cells upon their activation14. However, the mechanisms underlying the impact of mitochondrial malfunction on lysosomes and lysosomal biogenesis remain unaddressed7.…”

“…Under acute mitochondrial stress, lysosomes become dysfunctional and TFEB relocates to the nucleus141516. The mechanisms linking these processes remain however not completely understood7.…”

Role of exosomes in the protection of cellular homeostasis

“…73 Mitochondrial respiration is absolutely required for lysosomal degradation since in cells that relay on glycolysis as a consequence of mitochondrial dysfunction, there is an impairment of lysosomal degradation and function. 74 Lysosomes may also act as secretory organelles in multiples cell types. 75 Lysosome release their content to plasma membrane as a mechanism for defense against Figure 1.…”

Tumor Microenvironment Metabolism: A New Checkpoint for Anti-Tumor Immunity

“…Lysosomes are important for mTORC1 activation and further downstream signaling, but the effects of the loss of TFEB in T cells are still unknown. However, transcription factor A mitochondrial (TFAM) has also been shown to play a role in T cell lysosomal function [58]. Deletion of TFAM in T cells impairs lysosomal function and promotes proinflammatory T cell differentiation, linking T cell homeostasis with differentiation.…”