Cleaning up dmaged mitochondria is a key function of lysosomes. Skeletal muscle is particularly prone to damage to mitochondria that puts a strain on autophagy such that the lysosome portoion of phagosomes needs to be blebbed off and recycled in an alternative pathway. The PIP that regulates CIC7 is phosphorylated on positions [3,5] not positions [4,5] that are required for the alternative pathway. First we must take in a few lessions.
Lesson #1 PIP family members are inter-connected 
Kalpana Mandal of the Institute for Medicine and Engineering, University of Pennsylvania wrote a review on the phosphoinositide family of phospholipids. The inositol may have a variable number of phosphates on it.
Say, for instance PI[3,5]P2 has lower affinity for the N359R version of CIC7 and we need more PI[3,5] to turn it off, we can look into activators of the PIKfyve kinase. Conversely, say the N359R version of CIC7 is sucking up all of the PtIns in the lysosome, could a PTEN activator help restore PI[4,5] needed to recycle lysosomes in skeletal muscle? The latter seems to be unlikely.
The Mandal review covered a a lot of information on actin dynamics are are pertinent but the enormous volume of actin in skeletal muscle makes the discussion complicated. Figure 7 of the Mandal review makes the case for different flavers of PIP being responsible for vesicle trafficking.
CCP are clathrin coated pits. Clathrin is a protein coat that plays a role in intra cellular vesicle trafficking. MVB are multivesicular bodies that include autophagolysosomes.
Lesson #2 What doesn’t get digested is exocytosed.
This review by Samie and Xu came out of Department of Molecular, Cellular, and Developmental Biology, University of Michigan. The focus of the review was on lipid storage diseases.  These authors discussed how fusion of lysosomal cargo is detected: (1) electrode coding of TRPML1 Ca2+ that aids in membrane fusion, Lamp1 that assists in membrane fusion, and (3) release of enzymes. . 
Key points in this review
- Each cell contains several 100 that are about 5% of total cell volume
- filled with more than 50 different types of hydrolases: sulphatases, phosphatases,
lipases, proteases, carbohydrases, and glycosidases,
- The pH is maintained by the vacuolarATPase (V-ATPase)… proton pumps located on the perimeter
limited membrane inner leaflet of the lysosomal membrane is coated with a polysaccharide layer called the glycocalyx.
- Different cargos are delivered to lysosomes
- Autophagosomes deliver misfolded proteins and worn out organelles. Note, mitochondria might be particularly prone to wearing out in skeletal muscle.
- Degradation products are used in biosynthetic pathways or further metabolized\
- Lysosomes contain the lysosomal nutrient sensing system (LYNUS) that consists of V-ATPase, Rag GTPases, and the mammalian target of rapamycin (mTOR) complex.
The review got into the roles of PI(3,5)P2 and PI(4,5)P2 in facilitating the radius of curvature needed for membrane fusion, recruitment of effector proteins, and such as that. What really was not discussed in this review was the effect of local pH on all of these miraculous fusion events that PI(3,5)P2 and/or PI(4,5)P2 seem to be part of. The V-ATPse pumps H+ in so that is not going to change much.
Defective lysosome reformation during autophagy causes skeletal muscle disease
- Autophagy is defined as a process in which autophagosomes fuse with multiple lysosomes for the purpose of digesting cellular debris.
- Repopulation of the lysosome once the material in the autophago-lysome is digested.
- Skeletal muscle in particular is particularly dependent on this process because it is more likely to encounter structural damage and mitochondrial damage, and just because skeletal muscle can stand as a source of nutrients during fasting.
- The fasting inhibited mTOR is essential for autophagosome formation. mTOR is a serine/threonine kinase that senses nutrient availability, oxidative stress, and ATP availability. In short, mTOR integrates whether it is a good time for the ribosomes to be translating mRNAs into proteins.
- mTOR is also a serine/threonine kinase that phosphorylates that MITF transcription family members TFEB and TFE3. Nearly all proteins required for lysosome biogenesis are under the transcriptional control of TFEB, a master regulator of the lysosomal system.
- Other reports state that the Tfeb and/or Tfe3 genes in skeletal muscle alters mitochondrial biogenesis and affects metabolism but does not cause autophagy inhibition or muscle disease.
- Rather than synthesis of new lysosome proteins, autophagic lysosome reformation (ALR) is an alternative pathway for lysosome generation during autophagy, by which existing membranes derived from autolysosomes are recycled to generate new lysosomes.
- Under conditions of prolonged autophagy activation, cargo degradation within autolysosomes results in local amino acid release, initiating mTOR reactivation and the “go ahead” signal to permit mRNA translation to proteins.
- This same mTOR activation suppresses autophagy and promotes ALR.
- After ALR induction, autolysosomes extrude tubular membrane structures including phosphatidylinositol 4-phosphate [PI(4)P] and phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2], pl that were involved in the initial autophagosome-lysosome fusion.
- The synthesis of PI(4)P and PI(4,5)P2 on autolysosomes via the sequential actions of PI-4 and PI(4)P-5 kinases, respectively, is required for the initiation and progression of ALR.
- Localized generation of PI(4,5)P2-enriched microdomains on autophagolysosomes leads to the recruitment of effector proteins, which drive the formation of tubules that can break off to form new lysosomes. Do these pathways exist in whole animals?
- Inpp5k is an inositol polyphosphate 5-phosphatase that hydrolyzes PI(4,5)P2 to PI(4)P and, with reduced affinity, PI(3,4,5)P3 to PI(3,4)P2.
- Missense INPP5K mutations are causative for congenital muscular dystrophy overlapping with Marinesco-Sjögren syndrome (MSS), in which affected individuals exhibit a constellation of clinical manifestations, including muscular dystrophy, cataracts, and variable penetrance of brain abnormalities. The majority of these mutations map to the 5-phoshatase domain, reducing catalytic function toward PI(4,5)P2 by approximately 50%–75%.
- Muscular dystrophy caused by INPP5K mutations shows features suggestive of autophagy inhibition, including the accumulation of rimmed vacuoles, p62/SQSTM1,and αB-crystallin, but whether autophagy is impaired remains unresolved.
- INPP5K loss of function caused severe and progressive muscle disease, accompanied by marked lysosome depletion and autophagy inhibition. This occurred because of reduced conversion of PI(4,5)P2 to PI(4)P on autolysosomes, which impaired ALR progression.
What does this have to do with mutations in the CLCN7 gene?
- As discussed in a previous post, CIC7 copurifed with phosphatidylinositol with a phosphate at the 3rd position of inositol. Many possible variation of PIP phosphorylation occur in living systems. These variants are involved in membrane vesicle trafficking that includes lysomes. 
- Defects of vesicle trafficking define lysosomal storage disorders.
- Skeletal muscle is particularly dependent on the process of autophagy to clear away damaged structural proteins and mitochondria. Recycling of lysosomes in muscle involved a phosphatase that removes the phosphate from the 5′ postion of PI[4,5]P2. 
These have to do with a membrane bound H+/Cl– antiporter because the phosphates are charged groups whose charge depends on the pH. At 15 minute search failed to find information on the pKa of PIP family members. The pKa is the pH at which half of the groups are protonted. Let us assume that at neutral pH, some of th phosphates are charged. In the image below, three hydrogens were removed from PI[3,5]PIP2 going from –OH to –O– …. These negative charges are predicted to push the head groups away from each other allowing for a very curved surface. These same phosphate groups are predicted to be fully protonated in the vicinity of CIC7. Hypothetically speaking, when the phosphates are uncharged and pack more easily in a linear membrane structure.
This hypothesis explains how CIC7 mutations can affect vesicle trafficking and lysosomal pH. Perhaps minor mutations in non essential regions, such as N359R in the dimer interface, might not result in osteoporosis but could mess up things in skeletal muscle where autophagolysosome activity is at its highest.  Perhaps just a little structural wonkiness can mess things up in regions in which autophagy is in full gear. We really don’t know how much the N359R mutation affects dimr stability and if the dimer is even needed for full, PI[3,5]P2 regulated function discussed in a previous post.
If any of this hypothesis is correct, perhaps avoiding situations that cause muscle damage and cytosolic acidification would help maybe a little.
- Mandal K. Review of PIP2 in Cellular Signaling, Functions and Diseases. Int J Mol Sci. 2020 Nov 6;21(21):8342. PMC free article
- Samie MA, Xu H. Lysosomal exocytosis and lipid storage disorders. J Lipid Res. 2014 Jun;55(6):995-1009. doi: 10.1194/jlr.R046896. Epub 2014 Mar 25. PMC free paper
- McGrath MJ, Eramo MJ, Gurung R, Sriratana A, Gehrig SM, Lynch GS, Lourdes SR, Koentgen F, Feeney SJ, Lazarou M, McLean CA, Mitchell CA. Defective lysosome reformation during autophagy causes skeletal muscle disease. J Clin Invest. 2021 Jan 4;131(1):e135124.PMC free article
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